Antagonists of MCP-1 function and methods of use thereof

ABSTRACT

Chemical compounds which are antagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function, pharmaceutical compositions comprising these compounds, methods of treatment employing these compounds and compositions, and processes for preparing these compounds. The compounds are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Orohn&#39;s disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority under 35 USC 119(e) of U.S.Provisional Application No. 60/281,274, filed Apr. 3, 2001, which isincorporated into this application by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to chemical compounds,pharmaceutical compositions comprising said compounds, uses of saidcompounds and compositions, methods of treatment employing saidcompounds and compositions, and processes for preparing said compounds.Specifically, this invention relates to novel compounds which areantagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function andare useful in the prevention or treatment of chronic or acuteinflammatory or autoimmune diseases, especially those associated withaberrant lymphocyte or monocyte accumulation such as arthritis, asthma,atherosclerosis, diabetic nephropathy, inflammatory bowel disease,Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonaryfibrosis, psoriasis, restenosis, and transplant rejection. Morespecifically, the invention is related to pharmaceutical compositionscomprising these compounds and the use of these compounds andcompositions in the prevention or treatment of such diseases.

BACKGROUND OF THE INVENTION

[0003] Chemokines: Structure and Function

[0004] The migration of leukocytes from blood vessels into diseasedtissues is an important process in the initiation of normal inflammatoryresponses to certain stimuli or insults to the immune system. However,this process is also involved in the onset and progression oflife-threatening inflammatory and autoimmune diseases; blockingleukocyte recruitment in these disease states, therefore, can be aneffective therapeutic strategy.

[0005] The mechanism by-which leukocytes leave the bloodstream andaccumulate at inflammatory sites involves three distinct steps: (1)rolling, (2) arrest and firm adhesion, and (3) transendothelialmigration [Springer, Nature 346:425-433 (1990); Lawrence and Springer,Cell 65:859-873 (1991); Butcher, Cell 67:1033-1036 (1991)]. The secondstep is mediated at the molecular level by chemoattractant receptors onthe surface of leukocytes which bind chemoattractant cytokines secretedby proinflammatory cells at the site of damage or infection. Receptorbinding activates leukocytes, increases their adhesiveness to theendothelium, and promotes their transmigration into the affected tissue,where they can secrete inflammatory and chemoattractant cytokines anddegradative proteases that act on the subendothelial matrix,facilitating the migration of additional leukocytes to the site ofinjury.

[0006] The chemoattractant cytokines, collectively known as“chemokines,” are a large family of low molecular weight (8 to 10 kD)proteins that share the ability to stimulate directed cell migration(“chemotaxis”) [Schall, Cytokine 3:165-183 (1991); Murphy, Rev Immun12:593-633 (1994)].

[0007] Chemokines are characterized by the presence of four conservedcysteine residues and are grouped into two main subfamilies based onwhether the two amino-terminal cysteines are separated by one amino acid(CXC subfamily, also known as α-chemokines) or immediately adjacent toeach other (CC subfamily, also referred to as β-chemokines) [Baggioliniet al., Adv Immunol 55:97-179 (1994); Baggiolini et al., Annu RevImmunol 15:675-705 (1997); Deng et al., Nature 381:661-666 (1996);Luster, New Engl J Med 338:436445 (1998); Saunders and Tarby, DrugDiscovery Today 4:80-92 (1 999)].

[0008] The chemokines of the CXC subfamily, represented by IL-8, areproduced by a wide range of cells and act predominantly on neutrophilsas mediators of acute inflammation. The CC chemokines, which includeMCP-1, RANTES, MIP-1α, and MIP-1β, are also produced by a variety ofcells, but these molecules act mainly on monocytes and lymphocytes inchronic inflammation.

[0009] Like many cytokines and growth factors, chemokines utilize bothhigh and low affinity interactions to elicit full biological activity.Studies performed with labeled ligands have identified chemokine bindingsites (“receptors”) on the surface of neutrophils, monocytes, T cells,and eosinophils with affinities in the 500 pM to 10 nM range [Kelvin etal., J Leukoc Biol 54:604-612 (1993); Murphy, Annu Rev Immunol12:593-633 (1994); Raport et al., J Leukoc Biol 59:18-23 (1996); Premackand Schall, Nature Med 2:1174-1178 (1996)]. The cloning of thesereceptors has revealed that cell surface high-affinity chemokinereceptors belong to the seven transmembrane (“serpentine”)G-protein-coupled receptor (GPCR) superfamily.

[0010] Chemokine receptors are expressed on different cell types,including non-leukocyte cells. Some receptors are restricted to certaincells (e.g., the CXCR1 receptor is predominantly restricted toneutrophils), whereas others are more widely expressed (e.g., the CCR2receptor is expressed on monocytes, T cells, natural killer cells,dendritic cells, and basophils).

[0011] Given that at least twice as many chemokines have been reportedto date as there are receptors, there is a high degree of redundancy inthe ligands and, not surprisingly, most chemokine receptors are ratherpromiscuous with regard to their binding partners. For example, bothMIP-1α and RANTES bind to the CCR1 and CCR5 receptors, while IL-8 bindsto the CXCR1 and CXCR2 receptors. Although most chemokines receptorsbind more than one chemokine, CC receptors bind only CC chemokines, andCXC receptors bind only CXC chemokines. This ligand-receptor restrictionmay be related to the structural differences between CC and CXCchemokines, which have similar primary, secondary, and tertiarystructures, but different quaternary structures [Lodi et al., Science263:1762-1767 (1994)].

[0012] The binding of chemokines to their serpentine receptors istransduced into a variety of biochemical and physiological changes,including inhibition of cAMP synthesis, stimulation of cytosolic calciuminflux, upregulation or activation of adhesion proteins, receptordesensitization and internalization, and cytoskeletal rearrangementsleading to chemotaxis [Vaddi et al., J Immunol 153:4721-4732 (1994);Szabo et al., Eur J Immunol 27:1061-1068 (1997); Campbell et al.,Science 279:381-384 (1998); Aragay et al., Proc Natl Acad Sci USA95:2985-2990 (1998); Franci et al., J Immunol 157:5606-5612 (1996);Aramori et al., EMBO J 16:4606-4616 (1997); Haribabu et al., J Biol Chem272:28726-28731 (1997); Newton et al., Methods Enzymol 287:174-186(1997)]. In the case of macrophages and neutrophils, chemokine bindingalso triggers cellular activation, resulting in lysozomal enzyme releaseand generation of toxic products from the respiratory burst [Newton etal., Methods Enzymol 287:174-186 (1 997); Zachariae et al., J Exp Med171:2177-2182 (1990); Vaddi et al., J Leukocyte Biol 55:756-762 (1994)].The molecular details of the chemokine-receptor interactions responsiblefor inducing signal transduction, as well as the specific pathways thatlink binding to the above mentioned physiological changes, are stillbeing elucidated. Notwithstanding the complexity of these events, it hasbeen shown that in the case of the MCP-1/CCR2 interaction, specificmolecular features of MCP-1 can induce different conformations in CCR2that are coupled to separate post-receptor pathways [Jarnagin et al.,Biochemistry 38:16167-16177 (1999)]. Thus, it should be possible toidentify ligands that inhibit chemotaxis without affecting othersignaling events.

[0013] In addition to their high-affinity seven transmembrane GPCRs,chemokines of both subfamilies bind to various extracellular matrixproteins such as the glycosaminoglycans (GAGs) heparin, chondroitinsulfate, heparan sulfate, and dermatan sulfate with affinities in themiddle nanomolar to millimolar range. These low-affinity chemokine-GAGinteractions are believed to be critical not only for conformationalactivation of the ligands and presentation to their high-affinityserpentine receptors, but also for the induction of stable chemokinegradients that may function to stimulate haptotaxis (i.e., the migrationof specific cell subtypes in response to a ligand gradient that isaffixed upon the surface of endothelial cells or embedded within theextracellular matrix) [VWitt and Lander, Curr Biol 4:394-400 (1994);Rot, Eur J Immunol 23:303-306 (1993); Webb et al., Proc Natl Acad SciUSA 90:7158-7162 (1993); Tanaka et al, Nature 361:79-82 (1993); Gilat etal., J Immunol 153:4899-4906 (1994)]. Similar ligand-GAG interactionshave been described for a variety of cytokines and growth factors,including the various members of the FGF family, hepatocyte growthfactor, IL-3 and IL-7, GM-CSF, and VEGF [Roberts et al., Nature332:376-378 (1988); Gilat et al., Immunol Today 17:16-20 (1996); Clarkeet al., Cytokine 7:325-330 (1995); Miao et al., J Biol Chem271:4879-4886 (1996); Vlodavsky et al., Cancer Metastasis Rev 15:177-186(1996)].

[0014] MCP-1 and Diseases

[0015] Chemokines have been implicated as important mediators ofallergic, inflammatory and autoimmune disorders and diseases, such asasthma, atherosclerosis, glomerulonephritis, pancreatitis, restenosis,rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis, multiplesclerosis, and transplant rejection. Accordingly, it has been postulatedthat the use of antagonists of chemokine function may help reverse orhalt the progression of these disorders and diseases.

[0016] In particular, elevated expression of MCP-1 has been observed ina number of chronic inflammatory diseases [Proost et al., Int J Clin LabRes 26:211-223 (1996); Taub, D. D. Cytokine Growth Factor Rev 7:355-376(1996)] including, but not limited to, rheumatoid arthritis [Robinson etal., Clin Exp Immunol 101:398-407 (1995); Hosaka et al., ibid.97:451-457 (1994); Koch et al., J Clin Invest 90:772-779 (1992);Villiger et al., J Immunol 149:722-727 (1992)], asthma [Hsieh et al., JAllergy Clin Immunol 98:580-587 (1996); Alam et al., Am J Respir CritCare Med 153:1398-1404 (1996); Kurashima et al., J Leukocyte Biol59:313-316 (1996); Sugiyama et al., EurRespir J 8:1084-1090 (1995)], andatherosclerosis [Yla-Herttuala et al., Proc Natl Acad Sci USA88:5252-5256 (1991); Nelken et al., J Clin Invest 88:1121-1127 (1991)].

[0017] MCP-1 appears to play a significant role during the early stagesof allergic responses because of its ability to induce mast cellactivation and LTC4 release into the airway, which directly induces AHR(airways hyper-responsiveness) [Campbell et al., J Immunol 163:2160-2167(1999)].

[0018] MCP-1 has been found in the lungs of patients with idiopathicpulmonary fibrosis and is thought to be responsible for the influx ofmononuclear phagocytes and the production of growth factors thatstimulate mesenchymal cells and subsequent fibrosis [Antoniades et al.,Proc Natl Acad Sci USA 89:5371-5375 (1992)]. In addition, MCP-1 is alsoinvolved in the accumulation of monocytes in pleural effusions which isassociated with both Mycobacterium tuberculosis infection and malignancy[Strieter et al., J Lab Clin Med 123:183-197 (1994)].

[0019] MCP-1 has also been shown to be constitutively expressed bysynovial fibroblasts from rheumatoid arthritis patients, and its levelsare higher in rheumatoid arthritis joints compared to normal joints orthose from other arthritic diseases [Koch et al., J Clin Invest90:772-779 (1992)]. These elevated levels of MCP-1 are probablyresponsible for the monocyte infiltration into the synovial tissue.Increased levels of synovial MIP-1α and RANTES have also been detectedin patients with rheumatoid arthritis [Kundel et al., J Leukocyte Biol59:6-12 (1996)].

[0020] MCP-1 also plays a critical role in the initiation anddevelopment of atherosclerotic lesions. MCP-1 is responsible for therecruitment of monocytes into atherosclerotic areas, as shown byimmunohistochemistry of macrophage-rich arterial wall [Yla-Herttuala etal., Proc NatlAcad Sci USA 88:5252-5256 (1991); Nelken et al., J ClinInvest 88:1121-1127 (1991)] and anti-MCP-1 antibody detection [Takeya etal., Human Pathol 24:534-539 (1993)]. LDL-receptor/MCP-1-deficient andapoB-transgenic/MCP-1-deficient mice show significantly less lipiddeposition and macrophage accumulation throughout their aortas comparedwith wild-type MCP-1 strains [Alcami et al., J Immunol 160:624-633(1998); Gosling et al., J Clin Invest 103:773-778 (1999); Gu et al.,Mol. Cell. 2:275-281 (1998); Boring et al., Nature 394:894-897 (1998).

[0021] Other inflammatory diseases marked by specific site elevations ofMCP-1 include multiple sclerosis (MS), glomerulonephritis, and stroke.

[0022] These findings suggest that the discovery of compounds that blockMCP-1 activity would be beneficial in treating inflammatory diseases.

[0023] Antagonists of Chemokine Function

[0024] Most chemokine antagonists reported to date are eitherneutralizing antibodies to specific chemokines or receptor-ligandantagonists, that is, agents that compete with specific chemokines forbinding to their cognate serpentine receptors but, unlike the chemokinesthemselves, do not activate these receptors towards eliciting afunctional response [Howard et al., Trend Biotechnol 14:46-51 (1996)].

[0025] The use of specific anti-chemokine antibodies has been shown tocurtail inflammation in a number of animal models (e.g., anti-MIP-1α inbleomycin-induced pulmonary fibrosis [Smith et al., Leukocyte Biol57:782-787 (1994)]; anti-IL-8 in reperfusion injury [Sekido et al.,Nature 365:654-657 (1995)], and anti-MCP-1 in a rat model ofglomerulonephritis [Wada et al,, FASEB J 10:1418-1425 (1996)]). In theMRL-lpr mouse arthritis model, administration of an MCP-1 antagonistsignificantly reduced the overall histopathological score after theearly onset of the disease [Gong et al., J Exp Med 186:131-137 (1997)].

[0026] A major problem associated with using antibodies to antagonizechemokine function is that they must be humanized before use in chronichuman diseases. Furthermore, the ability of multiple chemokines to bindand activate a single receptor forces the development of a multipleantibody strategy or the use of cross-reactive antibodies in order tocompletely block or prevent pathological conditions.

[0027] Several small molecule antagonists of chemokine receptor functionhave been reported in the scientific and patent literature [White, J.Biol Chem 273:10095-10098 (1998); Hesselgesser, J. Biol Chem273:15687-15692 (1998); Bright et al., Bioorg Med Chem Left 8:771-774(1998); Lapierre, 26th Natl Med Chem Symposium, June 14-18, Richmond(Va.), USA (1998); Forbes et al., Bioorg Med Chem Lett 10:1803-18064(2000); Kato et al., WO Patent 97/24325; Shiota et al., WO Patent97/44329; Naya et al., WO Patent 98/04554; Takeda Industries, JP Patent0955572 (1998); Schwender et al., WO Patent 98/02151; Hagmann et al., WOPatent 98/27815; Connor et al., WO Patent 98/06703; Wellington et al.,U.S. Pat. No. 6,288,103 B1 (2001)].

[0028] The specificity of the chemokine receptor antagonists, however,suggests that inflammatory disorders characterized by multiple orredundant chemokine expression profiles will be relatively morerefractory to treatment by these agents.

[0029] A different approach to target chemokine function would involvethe use of compounds that disrupt the chemokine-GAG interaction. Oneclass of such agents with potential therapeutic application wouldconsist of small organic molecules that bind to the chemokine lowaffinity GAG-binding domain.

[0030] Compounds of this class might not inhibit binding of thechemokine to its high-affinity receptor per se, but would disruptchemokine localization within the extracellular matrix and provide aneffective block for directed leukocyte-taxis within tissues. Anadvantage of this strategy is the fact that most CC and CXC chemokinespossess similar C-terminal protein folding domains that define theGAG-binding site, and, hence, such compounds would be more useful forthe treatment of inflammatory disorders induced by multiple,functionally redundant chemokines [McFadden and Kelvin, BiochemPharmacol 54:1271-1280 (1997)].

[0031] The use of small molecule drugs to bind cytokine ligands anddisrupt interactions with extracellular GAGs has been reported withFGF-dependent angiogenesis [Folkman and Shing, Adv Exp Med Biol313:355-364 (1992)]. For example, the heparinoids suramin and pentosanpolysulphate both inhibit angiogenesis under conditions where heparin iseither ineffective or even stimulatory [Welistein and Czubayko, BreastCancer Res Treat 38:109-119 (1996)]. In the case of suramin, theanti-angiogenic capacity of the drug has also been shown to be targetedagainst VEGF [Waltenberger et al., J Mol Cell Cardiol 28:1523-1529(1996)] which, like FGF, possesses heparin-binding domains similar tothose of the chemokines. Heparin or heparin sulphate has also been shownto directly compete for GAG interactions critical for T-cell adhesionmediated by MIP-1β in vitro [Tanaka et al., Nature 361:79-82 (1993)].

[0032] The entire disclosure of all documents cited throughout thisapplication are incorporated herein by reference.

SUMMARY OF THE INVENTION

[0033] The present invention relates to compounds that inhibitMCP-1-induced chemotaxis of human monocytic cells both in vitro and invivo. These novel MCP-1 antagonists are useful for the treatment ofinflammatory diseases, especially those associated with lymphocyteand/or monocyte accumulation, such as atherosclerosis, diabeticnephropathy, inflammatory bowel disease, Crohn's disease, multiplesclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis,restenosis, rheumatoid arthritis, and other chronic or acute autoimmunedisorders. In addition, these compounds can be used in the treatment ofallergic hypersensitivity disorders, such as asthma and allergicrhinitis, characterized by basophil activation and eosinophilrecruitment.

[0034] A first embodiment of the present invention provides compounds ofFormula I, Formula II, and Formula III:

[0035] where:

[0036] (A) In Formula I:

[0037] each of W, X and Y is independently selected from CR⁶R⁷, N—R⁷, O,or S provided that at least one of W, X, and Y is a non-carbon ringatom, and at least one of W, X, and Y is a carbon ring atom.

[0038] (B) In Formula II:

[0039] W and X are independently selected from C-R⁶ and N, and Y isselected from CR⁶R⁷, N—R⁷, O, or S, provided that:

[0040] (i) at least one of W, X, and Y is a non-carbon ring atom, and

[0041] (ii) when W is C—R⁶ and X is N, then Y is CR⁶R⁷.

[0042] (C) In Formula III:

[0043] W is selected from CR⁶R⁷, N—R⁷, O, or S, and X and Y areindependently selected from C—R⁶ and N, provided that:

[0044] (i) at least one of W, X, and Y is a non-carbon ring atom, and

[0045] (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷.

[0046] Z is N or C—R⁸;

[0047] each R¹, R², R⁶, and R⁸ is independently, hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR⁹,—SR⁹, —NR⁹R¹⁰, —NR⁹(carboxy(lower alkyl)), —C(═O)R⁹, —C(═O)OR⁹,—(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —OSO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, heteroaryl(loweralkyl), or R⁹ and Rlo together are —(CH₂)₄₋₆— optionally interrupted byone O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl))or N-(optionally substituted C₁₋₂ alkyl) group,

[0048] R³ and R⁴ are independently, hydrogen, lower alkyl, optionallysubstituted lower alkyl, optionally substituted aryl, or optionallysubstituted aryl(lower alkyl), or, together, are —(CH₂)₂₋₄—,

[0049] R⁵ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaryl(lower alkyl), optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl), —(═O)R¹¹, —(═O)OR¹¹, —(═O)NR¹¹R¹²,—SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² are independently,hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), aryl, optionally substitutedheteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹² together are—(CH₂)₄₋₆—,

[0050] each R⁷ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), —(═O)R⁹,—C(═O)OR⁹, —(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(loweralkyl), aryl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group,

[0051] or the pharmaceutically acceptable salts thereof, optionally inthe form of single stereoisomers or mixtures of stereoisomers thereof.

[0052] The compounds of this invention may possess one or more chiralcenters, and can therefore be produced as individual stereoisomers or asmixtures of stereoisomers, depending on whether individual stereoisomersor mixtures of stereoisomers of the starting materials are used. Inaddition, some of the compounds of the invention are capable of furtherforming pharmaceutically acceptable salts and esters. The compounds ofthis invention may further exist in tautomeric forms and can thereforebe produced as individual tautomeric forms or as mixtures of tautomericforms. Unless indicated otherwise, the description or naming of acompound or groups of compounds is intended to include both theindividual isomers or mixtures (racemic or otherwise) of stereoisomersand their tautomeric forms. Methods for the determination ofstereochemistry and the separation of stereoisomers are well known to aperson of ordinary skill in the art [see the discussion in Chapter 4 ofMarch J.: Advanced Organic Chemistry, 4th ed. John Wiley and Sons, NewYork, N.Y., 1992]. All of these stereoisomers and pharmaceutical formsare intended to be included within the scope of the present invention.

[0053] A second embodiment of the present invention provides compoundsof Formula Ia, Formula IIa, and Formula IIIa:

[0054] where:

[0055] (A) In Formula Ia:

[0056] each of W, X and Y is independently selected from CR⁶R⁷, N—R⁷, O,or S provided that at least one of W, X, and Y is a non-carbon ringatom, and at least one of W, X, and Y is a carbon ring atom.

[0057] (B) In Formula IIa:

[0058] W and X are independently selected from C—R⁶ and N, and Y isselected from CR⁶R⁷, N—R⁷, O, or S, provided that:

[0059] (i) at least one of W, X, and Y is a non-carbon ring atom, and

[0060] (ii) when W is C—R⁶ and X is N, then Y is CR⁶R⁷.

[0061] (C) In Formula IIIa:

[0062] W is selected from CR⁶R⁷, N—R⁷, O, or S, and X and Y areindependently selected from C—R⁶ and N, provided that:

[0063] (i) at least one of W, X, and Y is a non-carbon ring atom, and

[0064] (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷.

[0065] Z is N or C—R⁸;

[0066] R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as defined in the firstembodiment,

[0067] R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl,optionally substituted aryl, optionally substituted aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —CF₃, halo(lower alkyl),halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —(═O)R¹⁵ —(═O)OR¹⁵,—(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵,—SO₂R¹⁵,—SO₂NR¹⁵R¹⁶, —NR¹⁵SO₂R¹⁶ or—NR¹⁵C(=O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently, hydrogen,optionally substituted lower alkyl, alkenyl, alkynyl, —CF₃, cycloalkyl,optionally substituted heterocycloalkyl, cycloalkyl(lower alkyl),optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heteroarlyi(lower alkyl) or, together, are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl)group,

[0068] each R¹⁴ is independently selected from optionally substitutedlower alkyl, optionally substituted aryl, optionally substitutedheteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —(═O)R¹⁷,—(═O)OR¹⁷, —O(CH₂)_(m)C(═O)OR¹⁷, wherein m is an integer of 1 to 4, or—C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently, hydrogen, loweralkyl, alkenyl, alkynyl, —CF₃, optionally substituted heterocycloalkyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, heteroaryl(lower alkyl) or, together, are —(CH2)₄₋₆—,optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, and

[0069] where n is an integer of 0 to 4,

[0070] or the pharmaceutically acceptable salts thereof, optionally inthe form of single stereoisomers or mixtures of stereoisomers thereof.

[0071] Within this invention, certain compounds are preferred. Suchpreferred compounds are:

[0072] 1. compounds of Formula I or Ia where W and Y are O, X is CR⁶R⁷,where R⁶ and R⁷ are independently hydrogen, lower alkyl, or optionallysubstituted aryl, and Z is C—H; or

[0073] 2. compounds of Formula II or IIa where W is N, X is CR⁶, whereR⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y is O, andZ is C—H; or

[0074] 3. compounds of Formula III or IIIa where W is O, X is CR⁶, whereR⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y is N, andZ is C—H; or

[0075] 4. compounds of Formula III or IIIa where W is N—R⁷, where R⁷ ishydrogen, lower alkyl, substituted lower alkyl, or optionallysubstituted aryl(lower alkyl), X and Y are each CR⁶, where R⁶ ishydrogen, lower alkyl, or optionally substituted aryl, and Z is C—H; or

[0076] 5. compounds of Formula II or IIa where W and X are each CR⁶,where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y isN—R⁷, where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, oroptionally substituted aryl(lower alkyl), and Z is C—H; or

[0077] 6. compounds of Formula II or IIa, where W and X are each N, Y isN—R⁷, where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, oroptionally substituted aryl(lower alkyl), and Z is C—H; or

[0078] 7. compounds of Formula I or Ia where W and X are each CR⁶R⁷,where R⁶ and R⁷ are independently hydrogen, lower alkyl, or optionallysubstituted aryl, Y is O, and Z is C—H; or

[0079] 8. compounds of Formula I or Ia, where W is O, X and Y are eachCR⁶R⁷, where R⁶ and R⁷ are independently hydrogen, lower alkyl, oroptionally substituted aryl, and Z is C—H; or

[0080] 9. compounds of Formula II or IIa where W is N, X is CR⁶, whereR⁶ is hydrogen, lower alkyl, or optionally substituted aryl, Y is N—R⁷,where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, oroptionally substituted aryl(lower alkyl), and Z is C—H; or

[0081] 10. compounds of Formula III or IIIa where W is N—R⁷, where R⁷ ishydrogen, lower alkyl, substituted lower alkyl, or optionallysubstituted aryl(lower alkyl), X is CR⁶, where R⁶ is hydrogen, loweralkyl, or optionally substituted aryl, Y is N, and Z is C—H; or

[0082] 11. compounds of Formula III or IIIa where W is N—R⁷, where R⁷ ishydrogen, lower alkyl, substituted lower alkyl, or optionallysubstituted aryl(lower alkyl), X and Y are each N, and Z is C—H; or

[0083] 12. compounds of the first and second embodiments where R¹ and R²are independently selected from hydrogen, lower alkyl, halogen,optionally lower alkyl substituted heterocycloalkyl, —OR⁹, —SR⁹, or—NR⁹R¹⁰, wherein R⁹ and R¹⁰ are hydrogen, lower alkyl or optionallysubstituted aryl; and/or

[0084] 13. compounds of the first and second embodiments where R³ and R⁴are independently selected from hydrogen or lower alkyl; or

[0085] 14. compounds of Formula I or Ia where W and X are each CR⁶R⁷,where R⁶ and R⁷ are independently hydrogen, lower alkyl, or optionallysubstituted aryl, and Z is N—R⁷; or

[0086] 15. compounds of Formula I or Ia where W is CR⁶R⁷, where R⁶ andR⁷ are independently hydrogen, lower alkyl, or optionally substitutedaryl, X is O, and Z is N—R⁷; or

[0087] 16. compounds of Formula I or Ia where W is O, X is CR⁶R⁷, whereR⁶ and R⁷ are independently hydrogen, lower alkyl, or optionallysubstituted aryl, and Z is N—R⁷.

[0088] Compounds of the second embodiment are preferred. Within thesecond embodiment, preferred compounds are those where:

[0089] 17. R¹³ is independently selected from optionally substitutedaryl, optionally substituted heteroaryl, halogen, —CF₃, —CN,—OR¹⁵,—C(═)R¹⁵, —C(═O)OR¹⁵, or —(═O)NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁵ areindependently, hydrogen, lower alkyl, halo(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, heteroaryl(loweralkyl) or R¹⁵ and R¹⁶ together are —(CH₂)₄₋₆—, optionally interrupted byone O, S, NH or N—(C₁₋₂ alkyl) group, such as piperazinyl,4-methylpiperazin-1-yl, morpholyl, hexahydropyrimidyl, and the like;and/or

[0090] 18. each R¹⁴ is independently selected from halogen, —CF₃, —OR¹⁷,—(═O)OR¹⁷, —O(CH₂)_(m)C(═O)OR¹⁷ wherein m is an integer of 1 to 4, or—(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently, hydrogen, loweralkyl, optionally substituted aryl, heteroaryl, or heteroaryl(loweralkyl), or R¹⁷ and R¹⁸ together are —(CH₂)₄₋₆—, optionally interruptedby one O, S, NH or N—(C₁₋₂ alkyl) group, such as piperazinyl,4-methylpiperazin-1-yl, morpholyl, and the like.

[0091] A number of different preferences have been given above, andfollowing any one of these preferences results in a compound of thisinvention that is more presently preferred than a compound in which thatparticular preference is not followed. However, these preferences aregenerally independent [although preferences 1-11 above are mutuallyexclusive], and additive; and following more than one of thesepreferences may result in a more presently preferred compound than onein which fewer of the preferences are followed.

[0092] A third embodiment of the present invention providespharmaceutical compositions comprising a pharmaceutically acceptableexcipient and a therapeutically effective amount of at least onecompound of this invention.

[0093] A fourth embodiment of the present invention provides methods fortreating diseases treatable by administration of an MCP-1 inhibitor, forexample, chronic or acute inflammatory or autoimmune diseases such asasthma, atherosclerosis, diabetic nephropathy, glomerulonephritis,inflammatory bowel disease, Crohn's disease, multiple sclerosis,pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoidarthritis, or a transplant rejection in mammals in need thereof,comprising the administration to such mammal of a therapeuticallyeffective amount of at least one compound of this invention or apharmaceutically acceptable salt thereof or a pharmaceutical compositioncomprising the same.

[0094] A fifth embodiment of this invention provides processes for thepreparation of the compounds of the invention and the pharmaceuticallyacceptable salts thereof.

[0095] A sixth embodiment of this invention provides uses of thecompounds of the invention in the preparation of medicaments for thetreatment of chronic or acute inflammatory or autoimmune diseases suchas asthma, atherosclerosis, diabetic nephropathy, glomerulonephritis,inflammatory bowel disease, Crohn's disease, multiple sclerosis,pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoidarthritis, or a transplant rejection.

DETAILED DESCRIPTION OF THE INVENTION

[0096] Definitions and General Parameters

[0097] The following definitions apply to the description of compoundsof the present invention:

[0098] “Alkyl” is a linear or branched saturated hydrocarbon radicalhaving from 1 to 20 carbon atoms. Examples of alkyl radicals are:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl, dodecyl, etc.

[0099] “Lower alkyl”, as in “lower alkyl,” “lower alkoxy,”“cycloalkyl(lower alkyl),” “aryl(lower alkyl)”, or “heteroaryl(loweralkyl)”, means a C₁₋₁₀ alkyl radical. Preferred lower alkyl radicals arethose having from 1 to 6 carbon atoms.

[0100] “Alkenyl” is a linear or branched hydrocarbon radical having from2 to 20 carbon atoms and at least one carbon-carbon double bond.Examples of alkenyl radicals are: vinyl, 1-propenyl, isobutenyl, etc.

[0101] “Alkynyl” is a linear or branched hydrocarbon radical having from2 to 20 carbon atoms and at least one carbon-carbon triple bond.Examples of alkynyl radicals are: propargyl, 1-butynyl, etc.

[0102] “Cycloalkyl” is a monovalent cyclic hydrocarbon radical havingfrom 3 to 12 carbon atoms. Examples of cycloalkyl radicals are:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0103] “Substituted cycloalkyl” is a monovalent cyclic hydrocarbonradical having from 3 to 12 carbon atoms, which is substituted with one,two, or three substituents each independently selected from aryl,substituted aryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, —NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently,hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(loweralkyl), substituted aryl(lower alkyl), heteroaryl, or heteroaryl(loweralkyl), and having 3 to 12 ring atoms, 1 to 5 of which are heteroatomschosen, independently, from N, O, or S, and includes monocyclic,condensed heterocyclic, and condensed carbocyclic and heterocyclic rings(e.g., piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl [perhydro-1,4-diazepinyl],etc.).

[0104] “Cycloalkyl(lower alkyl)” is a lower alkyl radical which issubstituted with a cycloalkyl, as previously defined. Examples ofcycloalkyl(lower alkyl) radicals are cyclopropylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, etc.

[0105] “Heterocycloalkyl” is a monovalent cyclic hydrocarbon radicalhaving 3 to 12 carbon ring atoms, 1 to 5 of which are heteroatomschosen, independently, from N, O, or S, and includes monocyclic,condensed heterocyclic, and condensed carbocyclic and heterocyclic rings(e.g., piperidyl, 4-morpholyi, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

[0106] “Substituted heterocycloalkyl” is a monovalent cyclic hydrocarbonradical having from 3 to 12 carbon atoms, which is substituted with one,two, or three substituents each independently selected from aryl,substituted aryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, —NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently,hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(loweralkyl), substituted aryl(lower alkyl), heteroaryl, or heteroaryl(loweralkyl), and having 3 to 12 ring atoms, 1 to 5 of which are heteroatomschosen, independently, from N, O, or S, and includes monocyclic,condensed heterocyclic, and condensed carbocyclic and heterocyclic rings(e.g., piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

[0107] “Substituted heterocycloalkyl(lower alkyl)” is a lower alkylradical which is substituted with a monovalent cyclic hydrocarbonradical having from 3 to 12 carbon atoms, which is substituted with one,two, or three substituents each independently selected from aryl,substituted aryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, —NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently,hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(loweralkyl), substituted aryl(lower alkyl), heteroaryl, or heteroaryl(loweralkyl), and having 3 to 12 ring atoms, 1 to 5 of which are heteroatomschosen, independently, from N, O, or S, and includes monocyclic,condensed heterocyclic, and condensed carbocyclic and heterocyclic rings(e.g., piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

[0108] “Substituted alkyl” or “substituted lower alkyl,” is an alkyl orlower alkyl radical, respectively, which is substituted with one, two,or three substituents each independently selected from aryl, substitutedaryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′, or —PO₃HR, wherein R and R′ are, independently, hydrogen,lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl).

[0109] “Halo(lower alkyl)” is a radical derived from lower alkylcontaining at least one halogen substituent. Non-limiting examples ofhalo(lower alkyl) radicals include: —CF₃, C₂F₅, etc..

[0110] “Aryl”, as in “aryl”, “aryloxy”, and “aryl(lower alkyl)”, is aradical derived from an aromatic hydrocarbon containing 6 to 16 ringcarbon atoms, having a single ring (e.g., phenyl), or two or morecondensed rings, preferably 2 to 3 condensed rings (e.g., naphthyl), ortwo or more aromatic rings, preferably 2 to 3 aromatic rings, which arelinked by a single bond (e.g., biphenyl). Preferred aryl radicals arethose containing from 6 to 14 carbon atoms.

[0111] “Substituted aryl” is an aryl radical which is substituted withone, two, or three substituents each independently selected from alkyl,substituted alkyl, halo(lower alkyl), halogen, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —PO₃H₂,—NRSO₂R′, —C(═O)NRR′ or —NRC(═O)R′, wherein R and R′ are, independently,hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, aryl,substituted aryl, optionally substituted aryl(lower alkyl), heteroaryl,or heteroaryl(lower alkyl). Preferred substituted aryl radicals arethose substituted with one, two, or three substituents eachindependently selected from the group consisting of lower alkyl,halogen, —CF₃, nitro, —CN, —OR, —NRR′, —C(═O)NRR′, —SO₂OR,—SO₂NRR′,—PO₃H₂, —NRSO₂R′ or —NRC(═O)R′.

[0112] “Heteroaryl”, as in “heteroaryl” and “heteroaryl(lower alkyl)”,is a radical derived from an aromatic hydrocarbon containing 5 to 14ring atoms, 1 to 5 of which are heteroatoms chosen, independently, fromN, O, or S, and includes monocyclic, condensed heterocyclic, andcondensed carbocyclic and heterocyclic aromatic rings (e.g., thienyl,furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl,isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, imidazolyl, pyridyl,pyrazolyl, pyrazinyl, quinolyl, etc.).

[0113] “Substituted heteroaryl” is a heteroaryl radical which issubstituted with one, two, or three substituents each independentlyselected from alkyl, substituted alkyl, halogen, CF₃, nitro, —CN, —OR,—SR, —NRR′, —C(═O)R, OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR ,—NRSO₂R′, —C(═O)NRR′, or —NRC(═O)R′, wherein R and R′ are,independently, hydrogen, lower alkyl, substituted lower alkyl,cycloalkyl, aryl, substituted aryl, aryl(lower alkyl), substitutedaryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl). Particularlypreferred substituents on the substituted heteroaryl moiety includelower alkyl, substituted lower alkyl, halo(lower alkyl), halogen, nitro,—CN, —OR, —SR, and —NRR′.

[0114] “Aryl(lower alkyl)” is a lower alkyl radical which is substitutedwith an aryl, as previously defined.

[0115] “Substituted aryl(lower alkyl)” is an aryl(lower alkyl) radicalhaving one to three substituents on either or both of the aryl and thealkyl portion of the radical.

[0116] “Heteroaryl(lower alkyl)” is a lower alkyl radical which issubstituted with a heteroaryl, as previously defined.

[0117] “Substituted heteroaryl(lower alkyl)” is a heteroaryl(loweralkyl) radical having one to three substituents on the heteroarylportion or the alkyl portion of the radical, or both.

[0118] “Lower alkoxy” is an —OR radical, where R is a lower alkyl orcycloalkyl.

[0119] “Halogen” means fluoro, chloro, bromo, or iodo.

[0120] “Stereoisomers” are compounds that have the same sequence ofcovalent bonds and differ in the relative disposition of their atoms inspace.

[0121] “Inner salts” or “Zwitterions” are compounds wherein the positiveand negative groups, such as amine and acid groups within the compound,are equally ionized. The compounds are charge separated species thatresult from the transfer of a proton from the acidic site to a basicsite, typically in a compound containing an amine and an acid group.

[0122] “Tautomers” are isomeric compounds that differ from one anotherby interchanged positions of σ and π bonds. The compounds are inequilibrium with one another. They may also differ from, one another inthe position at which a hydrogen atom is attached.

[0123] “Pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic, and desirable, and includes excipients that areacceptable for veterinary use as well as for human pharmaceutical use.Such excipients may be solid, liquid, semisolid, or, in the case of anaerosol composition, gaseous.

[0124] “Pharmaceutically acceptable salts and esters” means any salt andester that is pharmaceutically acceptable and has the desiredpharmacological properties. Such salts include salts that may be derivedfrom an inorganic or organic acid, or an inorganic or organic base,including amino acids, which is not toxic or undesirable in any way.Suitable inorganic salts include those formed with the alkali metals,e.g., sodium and potassium, magnesium, calcium, and aluminum. Suitableorganic salts include those formed with organic bases such as the aminebases, e.g., ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. Such salts also includeacid addition salts formed with inorganic acids (e.g., hydrochloric andhydrobromic acids) and organic acids (e.g., acetic acid, citric acid,maleic acid, and the alkane and arene-sulfonic acids such asmethanesulfonic acid and benzenesulfonic acid). Pharmaceuticallyacceptable esters include esters formed from carboxy, sulfonyloxy, andphosphonoxy groups present in the compounds, e.g., C₁₋₆ alkyl esters.When there are two acidic groups present, a pharmaceutically acceptablesalt or ester may be a mono-acid-mono-salt or ester or a di-salt orester; and similarly, where there are more than two acidic groupspresent, some or all of such groups can be salified or esterified.

[0125] “Therapeutically effective amount” means that amount which, whenadministered to a mammal for treating a disease, is sufficient to effectsuch treatment for the disease.

[0126] “Treating” or “treatment” of a disease in a mammal includes:

[0127] (1) Preventing the disease from occurring in a mammal which maybe predisposed to the disease but does not yet experience or displaysymptoms of the disease;

[0128] (2) Inhibiting the disease, i.e., arresting its development, or

[0129] (3) Relieving the disease, i.e., causing regression of thedisease.

[0130] “Disease” includes any unhealthy condition of an animal (whichincludes human and non-human mammals), including particularly variousforms of inflammatory illnesses or diseases, such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, immunedisorders, and transplant rejection.

[0131] The Compounds and Their Pharmaceutically Acceptable Salts

[0132] The first embodiment of the present invention provides compoundsof Formula I, Formula II, and Formula III:

[0133] where W, X, Y. Z. and R¹ to R⁵ are as defined above,

[0134] or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.

[0135] Preferably, R¹ is hydrogen, optionally substituted lower alkyl,cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹[carboxy(loweralkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, optionally substituted loweralkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.

[0136] More preferably, R¹ is optionally substituted lower alkyl,cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹[carboxy(loweralkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, optionally substituted loweralkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.

[0137] Preferably, R² is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or—C(═O)NR⁹R¹⁰, wherein R9 and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, heteroaryl(lower alkyl), or R⁹ andR¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-[aryl(lower alkyl)], N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.

[0138] More preferably, R² is optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or—C(═O)NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-[aryl(lower alkyl)], N-[carboxy(lower alkyl)] or N-(optionallysubstituted C₁₋₂ alkyl) group.

[0139] Preferably, R³ and R⁴ are independently, hydrogen or lower alkyl,or together are —(CH₂)₂₋₄—. More preferably, R³ and R⁴ areindependently, hydrogen or lower alkyl.

[0140] Preferably, R⁵ is hydrogen, optionally substituted lower alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl, optionally substituted aryl, aryl(loweralkyl), optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, heteroaryl,heteroaryl(lower alkyl), or R¹¹ and R¹² together are —(CH₂)₄₋₆—.

[0141] Preferably, R⁶ and R⁷ are independently hydrogen, optionallysubstituted lower alkyl, alkenyl, cycloalkyl, cycloalkyl(lower alkyl),optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted aryl(lower alkyl), optionally substitutedheteroaryl, optionally substituted heteroaryl(lower alkyl), —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, cycloalkyl,cycloalkyl(lower alkyl), aryl, heteroaryl, heteroaryl(lower alkyl), orR⁹ and R¹⁰ together are —(CH₂)₄₋₆—.

[0142] More preferably, R⁶ and R⁷ are independently hydrogen, optionallysubstituted lower alkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aryl(lower alkyl), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, alkenyl, alkynyl, optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).

[0143] Preferably, R⁸ is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), —CF₃, halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, optionallysubstituted cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedaryl, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.

[0144] Where R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interruptedby one O, S, NH, N-(aryl), N-[aryl (lower alkyl)], N-[carboxy(loweralkyl)] or N-(optionally substituted C₁₋₂ alkyl) group, examples includepiperidinyl, piperazinyl, 4-methylpiperazinyl,4-(carboxymethyl)piperazinyl, 4-morpholyl, and hexahydropyrimidyl.

[0145] A particularly preferred “substituted aryl” is a phenyl groupsubstituted with R¹³ and optionally substituted with up to four R¹⁴s,where R¹³ and R¹⁴ are defined with respect to Formulae Ia, IIa and IIIa.

[0146] The above-listed preferences equally apply for the compounds ofFormulae Ia, IIa, and IIIa below.

[0147] In a more preferred version of the first embodiment of theinvention,

[0148] (A) in Formula I;

[0149] W and X are C—R⁶, Y is O, and Z is C—R⁸, or

[0150] W and Y are O, and Z is C—R⁸

[0151] In another more preferred version of the first embodiment of theinvention,

[0152] (B) in Formula II;

[0153] W is N, Y is O, and Z is C—R⁸, or

[0154] W and X are C—R⁶, Y is N—R⁷, and Z is C—R⁸, or

[0155] W and X are N, Y is N—R⁷, and Z is C—R⁸, or

[0156] W is N and Y is N—R⁷, and Z is C—R⁸.

[0157] In another more preferred version of the first embodiment of theinvention,

[0158] (C) in Formula III;

[0159] W is N—R⁷, and Z is C—R⁸, or

[0160] W is O and Y is N, and Z is C—R⁸. or

[0161] W is N—R⁷, and X and Y are C—R⁶, and Z is C—R⁸.

[0162] For (A), (B) and (C);

[0163] R¹, R³ and R⁴ are hydrogen, and

[0164] R⁵ is optionally substituted aryl or optionally substitutedheteroaryl. or a pharmaceutical acceptable salt thereof, optionally inthe form of a single stereoisomer or mixture of stereoisomers thereof.

[0165] In another more preferred version of the first embodiment of theinvention,

[0166] R² is hydrogen or chlorine,

[0167] R³ and R⁴ are hydrogen or lower alkyl, and

[0168] R⁵ is optionally substituted aryl or optionally substitutedheteroaryl,

[0169] or a pharmaceutical acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.

[0170] The second embodiment of the present invention provides compoundsof Formula Ia, Formula IIa, or Formula IIIa:

[0171] where:

[0172] (A) In Formula Ia:

[0173] each of W, X and Y is independently selected from CR⁶R⁷, N—R⁷, O,or S provided that at least one of W, X, and Y is a non-carbon ringatom, and at least one of W, X, and Y is a carbon ring atom.

[0174] (B) In Formula IIa:

[0175] W and X are independently selected from C—R⁶ and N, and Y isselected from CR⁶R⁷, N—R⁷, O, or S, provided that:

[0176] (i) at least one of W, X, and Y is a non-carbon ring atom, and

[0177] (ii) when W is C—R⁶ and X is N, then Y is CR⁶R⁷.

[0178] (C) In Formula IIIa:

[0179] W is selected from CR⁶R⁷, N—R⁷, O, or S, and X and Y areindependently selected from C—R⁶ and N, provided that:

[0180] (i) at least one of W, X, and Y is a non-carbon ring atom, and

[0181] (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷.

[0182] Z is N or C—R⁸;

[0183] R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as defined in the firstembodiment,

[0184] R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl,optionally substituted aryl, optionally substituted aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN,—OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═)NR¹⁵RR, —OC(═O)R¹⁵,—SO₂R¹⁵, —SO₂NR¹⁵R¹⁶ NR¹⁵SO₂R¹⁶ —NR¹⁵C(═O)R ⁶, wherein R¹⁵ and R¹⁶ areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, —CF₃, cycloalkyl, halo(lower alkyl), optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one 0, S, NH or N-(Cl₂ alkyl) group,

[0185] each R¹⁴ is independently selected from optionally substitutedlower alkyl, optionally substituted aryl, optionally substitutedheteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —C(═O)R¹⁷,—C(═O)OR¹⁷ —O(CH₂)_(m)C(═O)OR¹⁷, wherein m is an integer of 1 to 4, or—C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently, hydrogen, loweralkyl, alkenyl, alkynyl, —CF₃, optionally substituted heterocycloalkyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—,optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, and

[0186] where n is an integer of 0 to 4, and the pharmaceuticallyacceptable salts thereof, optionally in the form of single stereoisomersor mixtures of stereoisomers thereof.

[0187] Preferably, R¹, R², and R⁸ are optionally substituted loweralkyl, cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹[carboxy(loweralkyl)], —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, lower alkyl, or R⁹ and R¹⁰together are —CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group,

[0188] n is a stereocompatible integer of 0 to 4. The term“stereocompatible” limits the number of substituents permissible byavailable valences in accordance with space requirements of thesubstituents.

[0189] Preferably, R¹³ is hydrogen, optionally substituted lower alkyl,alkenyl, heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃,halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶,wherein R¹⁵ and R¹⁶ are independently, hydrogen, optionally substitutedlower alkyl, alkenyl, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group.

[0190] More preferably, R¹³ is optionally substituted lower alkyl,alkenyl, heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃,halogen, nitro, —CN, —OR ⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶,wherein R¹⁵ and R1⁶ are independently, hydrogen, optionally substitutedlower alkyl, alkenyl, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group.

[0191] Preferably, each R¹⁴ is independently selected from optionallysubstituted lower alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷ —NR¹⁷R¹⁸,—C(═O)R¹l, —C(═O)OR¹⁸, —C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are,independently, hydrogen, lower alkyl, alkenyl, or optionally substitutedaryl.

[0192] Preferably, where R¹³ is not hydrogen, n is an integer of 1 to 2.More preferably, where R¹³ is not hydrogen, n is 1.

[0193] In a more preferred version of the second embodiment of theinvention,

[0194] (A) in Formula Ia;

[0195] W and X are C—R⁶, Y is O, and Z is C—R⁸, or

[0196] W and Y are O, and Z is C—R⁸, each R¹³ and R¹⁴ is, independently,lower alkyl, alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, halo(lower alkyl), —CF₃, halogen, nitro, —OR¹⁵,—SR¹⁵, or —C(═O)NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently,hydrogen, optionally substituted lower alkyl, or —CF₃, or

[0197] W and X are CR⁶R⁷, Y is O, and each R¹³ and R¹⁴ is,independently, —CF₃, halogen, —OR¹⁵, wherein R¹⁵ is independently,hydrogen, optionally substituted lower alkyl,or —CF₃.

[0198] In another more preferred version of the second embodiment of theinvention,

[0199] (B) in Formula IIa;

[0200] W is N, Y is O, and Z is C—R⁸, and each R¹³ and R¹⁴ is,independently, —CF₃, halogen, or

[0201] W and X are C—R⁶, Y is N—R⁷, Z is C—R⁸, and each R¹³ and R¹⁴ is,independently, —CF₃, or halogen, or

[0202] W and X are N, Y is N—R⁷, Z is C—R⁸, and R¹³ and R¹⁴ are halogen,or

[0203] W is N and Y is N—R⁷, Z is C—R⁸, and R¹³ and R¹⁴ are halogen.

[0204] In another more preferred version of the second embodiment of theinvention,

[0205] (C) in Formula IIIa;

[0206] W is N—R⁷, Z is C—R⁸, and each R¹³ and R¹⁴ is, independently,—CF₃, halogen, or —CN, or

[0207] W is O and Y is N, Z is C—R⁸, and each R¹³ and R¹⁴ is,independently, halo(lower alkyl), —CF₃, halogen, nitro, —OR¹⁵, —SR¹⁵, or—CO₂R¹⁵, wherein R¹⁵ is hydrogen, or —CF₃, or

[0208] W is N—R⁷, and X and Y are C—R⁶, Z is C—R⁸, and each R¹³ and R¹⁴is, independently, —CF₃, halogen, or —CN,

[0209] More preferably still, R⁴ and R⁵ are hydrogen.

[0210] Most preferably, independently,

[0211] 1. For Formula Ia, W and Y is O, X is CR⁶R⁷, and Z is C—H.

[0212] 2. For Formula IIa, W is N, X is C—H, Y is O, and Z is C—H.

[0213] 3. For Formula IIa, W and X are C—H, Y is N—CH₃, and Z is C—H.

[0214] 4. For Formula IIa, W and X are N, Y is N—H, and Z is C—H.

[0215] 5. For Formula IIIa, W is O, X is C—H, Y is N, and Z is C—H.

[0216] 6. For Formula IIIa, W is N—CH₃, X is C—H, Y is N—CH₃, and Z isC—H.

[0217] 7. R¹, R³ and R⁴ are hydrogen.

[0218] 8. R² is hydrogen or chlorine.

[0219] 9. R¹³ and R¹⁴ are independently selected from lower alkyl,halogen, optionally substituted aryl, optionally substituted heteroaryl,—CF₃, nitro, —OCF₃, —SCF₃, halo(lower alkyl), —CN, —OR¹⁵, —C(═O)R¹⁵,—C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, or —CO₂HR

[0220] The preferred compounds of the invention are listed in Tables1-11 below.

[0221] The compounds of this invention may possess one or more chiralcenters, and can therefore exist as individual stereoisomers or asmixtures of stereoisomers. In such cases, all stereoisomers also fallwithin the scope of this invention. The compounds of this invention mayalso exist in various tautomeric forms, and in such cases, all tautomersalso fall within the scope of this invention. The invention compoundsinclude the individually isolated stereoisomers and tautomers as well asmixtures of such stereoisomers and their tautomers.

[0222] Some of the compounds of Formula I, Formula II, and Formula IIIare capable of further forming pharmaceutically acceptable salts andesters. All of these forms are included within the scope of the presentinvention.

[0223] Pharmaceutically acceptable base addition salts of the compoundsof Formula I, Formula II, and Formula III include salts which may beformed when acidic protons present in the parent compound are capable ofreacting with inorganic or organic bases. Typically, the parent compoundis treated with an excess of an alkaline reagent, such as hydroxide,carbonate, or alkoxide, containing an appropriate cation. Cations suchas Na⁺, K⁺, Ca²⁺, and NH₄ ⁺ are examples of cations present inpharmaceutically acceptable salts. The Na⁺ salts are especially useful.Acceptable inorganic bases, therefore, include aluminum hydroxide,calcium hydroxide, potassium hydroxide, sodium carbonate andsodium-hydroxide. Salts may also be prepared using organic bases, suchas choline, dicyclohexylamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, procaine, N-methylglucamine, and thelike [for a nonexclusive list see, for example, Berge et al.,“Pharmaceutical Salts,” J. Pharma. Sci. 66:1 (1977)]. The free acid formmay be regenerated by contacting the base addition salt with an acid andisolating the free acid in the conventional manner. The free acid formscan differ from AVtheir respective salt forms somewhat in certainphysical properties such as solubility in polar solvents.

[0224] Pharmaceutically acceptable acid addition salts of the compoundsof Formula I, Formula II, and Formula III include salts which may beformed when the parent compound contains a basic group. Acrid additionsalts of the compounds are prepared in a suitable solvent from theparent compound and an excess of a non-toxic inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfateand bisulfate salts), nitric acid, phosphoric acid and the like, or anon-toxic organic acid such as aceticacid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, salicylic acid, p-toluenesulfonic acid, hexanoic. acid, heptanoicacid, cyclopentanepropionic acid, lactic acid,o-(4-hydroxy-benzoyl)benzoic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,camphorsulfonic acid, 4-methyl-bicyclo[2.2.2.]oct-2-ene-1-carboxylicacid, glucoheptonic acid, gluconic acid,4,4′-methylenebis(3-hydroxy-2-naphthoic)acid, 3-phenylpropionic acid,trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid,glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearicacid, muconic acid, and the like. The free base form may be regeneratedby contacting the acid addition salt with a base and isolating the freebase in the conventional manner. The free base forms can differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents.

[0225] Also included in the embodiment of the present invention aresalts of amino acids such as arginate and the like, gluconate, andgalacturonate [see Berge, supra (1977)].

[0226] Some of the compounds of the invention may form inner salts orZwitterions.

[0227] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms,and are intended to be encompassed within the scope of the presentinvention.

[0228] Certain of the compounds of the present invention may also existin one or more solid or crystalline phases or polymorphs, the variablebiological activities of such polymorphs or mixtures of such polymorphsare also included in the scope of this invention.

[0229] Pharmaceutical Compositions

[0230] A third embodiment of the present invention providespharmaceutical compositions comprising pharmaceutically acceptableexcipients and a therapeutically effective amount of at least onecompound of this invention.

[0231] Pharmaceutical compositions of the compounds of this invention,or derivatives thereof, may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation is generally a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, 5% dextrose in water or buffered sodium orammonium acetate solution. Such formulations are especially suitable forparenteral administration but may also be used for oral administration.It may be desirable to add excipients such as polyvinylpyrrolidinone,gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodiumchloride, or sodium citrate.

[0232] Alternatively, these compounds may be encapsulated, tableted, orprepared in an emulsion or syrup for oral administration.Pharmaceutically acceptable solid or liquid carriers may be added toenhance or stabilize the composition, or to facilitate preparation ofthe composition. Liquid carriers include syrup, peanut oil, olive oil,glycerin, saline, alcohols, or water. Solid carriers include starch,lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate orstearic acid, talc, pectin, acacia, agar, or gelatin. The carrier mayalso include a sustained release material such as glyceryl monostearateor glyceryl distearate, alone or with a wax. The amount of solid carriervaries but, preferably, will be between about 20 mg to about 1 g perdosage unit.

[0233] The pharmaceutical preparations are made following theconventional techniques of pharmacy involving milling, mixing,granulation, and compressing, when necessary, for tablet forms; ormilling, mixing, and filling for hard gelatin capsule forms. When aliquid carrier is used, the preparation will be in the form of a syrup,elixir, emulsion, or an aqueous or non-aqueous suspension. Such a liquidformulation may be administered directly p.o. or filled into a softgelatin capsule.

[0234] Some specific examples of suitable pharmaceutical compositionsare described in Examples 7-9.

[0235] Typically, a pharmaceutical composition of the present inventionis packaged in a container with a label indicating the use of thepharmaceutical composition in the treatment of a disease such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, andtransplant rejection, or a chronic or acute immune disorder, or acombination of any of these disease conditions.

[0236] Methods of Use

[0237] A fourth embodiment of the present invention provides a methodfor treating a disease treatable by administration of an MCP-1inhibitor, for example, chronic or acute inflammatory disease such asasthma, atherosclerosis, diabetic nephropathy, glomerulonephritis,inflammatory bowel disease, Crohn's disease, multiple sclerosis,pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoidarthritis, or a chronic or acute immune disorder, or a transplantrejection in mammals in need thereof, comprising the administration tosuch mammal of a therapeutically effective amount of at least onecompound of Formula I, Formula Ia, Formula II, Formula IIa, Formula III,Formula IIa, or a pharmaceutically acceptable salt or ester thereof.

[0238] The compounds of the present invention inhibit chemotaxis of ahuman monocytic cell line (THP-1 cells) induced by human MCP-1 in vitro.This inhibitory effect has also been observed in vivo. The compoundshave been shown to reduce monocyte infiltration in athioglycollate-induced inflammation model in mice.

[0239] The compounds of the present invention have been found to preventthe onset or ameliorate symptoms in several animal models ofinflammation. For example, the compounds inhibited the infiltration ofED-1 positive cells into the glomeruli and reduced the amount of urinaryprotein excretion in an anti-Thy-1 antibody-induced model of nephritis.

[0240] The ability of the compounds of this invention to block themigration of monocytes and prevent or ameliorate inflammation, which isdemonstrated in the specific examples, indicates their usefulness in thetreatment and management of disease states associated with aberrantleukocyte recruitment.

[0241] The use of the compounds of the invention for treatinginflammatory and autoimmune disease by combination therapy may alsocomprise the administration of the compound of the invention to a mammalin combination with common anti-inflammatory drugs, cytokines, orimmunomodulators.

[0242] The compounds of this invention are thus used to inhibitleukocyte migration in patients which require such treatment. The methodof treatment comprises the administration, orally or parenterally, of aneffective quantity of the chosen compound of the invention, preferablydispersed in a pharmaceutical carrier. Dosage units of the activeingredient are generally selected from the range of 0.01 to 1000 mg/kg,preferably 0.01 to 100 mg/kg, and more preferably 0.1 to 50 mg/kg, butthe range will be readily determined by one skilled in the art dependingon the route of administration, age, and condition of the patient. Thesedosage units may be administered one to ten times daily for acute orchronic disease. No unacceptable toxicological effects are expected whencompounds of the invention are used in accordance with the presentinvention.

[0243] The invention compounds may be administered by any route suitableto the subject being treated and the nature of the subject's condition.Routes of administration include, but are not limited to, administrationby injection, including intravenous, intraperitoneal, intramuscular, andsubcutaneous injection, by transmucosal or transdermal delivery, throughtopical applications, nasal spray, suppository and the like, or may beadministered orally. Formulations may optionally be liposomalformulations, emulsions, formulations designed to administer the drugacross mucosal membranes or transdermal formulations. Suitableformulations for each of these methods of administration may be foundin, for example, “Remington: The Science and Practice of Pharmacy”, A.Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins,Philadelphia, Pa.

EXAMPLES

[0244] The following Examples serve to illustrate the preparation,properties, and therapeutic applications of the compounds of thisinvention. These Examples are not intended to limit the scope of thisinvention, but rather to show how to prepare and use the compounds ofthis invention.

[0245] Preparation of the Compounds of the Invention: General Procedures

[0246] The following general procedures may be employed for thepreparation of the compounds of the present invention.

[0247] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as theAldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.),Sigma (St. Louis, Mo.), or are prepared by methods well known to aperson of ordinary skill in the art, following procedures described insuch references as Fieser and Fieser's Reagents for Organic Synthesis,vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistryof Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers,1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York,N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wileyand Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

[0248] In some cases, protective groups may be introduced and finallyremoved. For example, suitable protective groups for amino, hydroxy, andcarboxy groups are described in Greene et al., Protective Groups inOrganic Synthesis, Second Edition, John Wiley and Sons, New York, 1991.Activation of carboxylic acids can be achieved by using a number ofdifferent reagents as described in Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

[0249] The starting materials, intermediates, and compounds of thisinvention may be isolated and purified using conventional techniques,including precipitation, filtration, distillation, crystallization,chromatography, and the like. The compounds may be characterized usingconventional methods, including physical constants and spectroscopicmethods.

[0250] Generally, a compound of Formula I, Formula II, or Formula III:

[0251] where n, W, X, Y, Z, and R¹- R⁵ are as defined in the firstembodiment, may be prepared by a process comprising:

[0252] (a) Contacting a compound of Formula Ib, Formula IIb, or FormulaIIIb:

[0253] with a compound of the formula

R⁵—N═C═O

[0254] under conditions sufficient to produce a compound of Formula I,Formula II, or Formula III, wherein R³ and R⁴ are both H; or

[0255] (b) Optionally, contacting a compound of Formula Ic, Formula IIc,or Formula IIIc:

[0256] wherein X is halogen, nitro, —CN, or —OR⁹, with a compound of theformula:

R¹—H

[0257] under conditions sufficient to produce a compound of Formula I,Formula II, or Formula III; or

[0258] (c) Contacting a compound of Formula Ib, Formula IIb, or FormulaIIIb:

[0259] with a haloformylation reagent and a compound of the formula:

[0260] under conditions sufficient to produce a compound of Formula I,Formula II, or Formula III, wherein R is H; or

[0261] (d) Elaborating substituents of a compound of Formula I, FormulaII, or Formula III in a manner known per se; or

[0262] (e) Reacting the free base of a compound of Formula I, FormulaII, or Formula III with an acid to give a pharmaceutically acceptableaddition salt; or

[0263] (f) Reacting an acid addition salt of a compound of Formula I,Formula II, or Formula III with a base to form the corresponding freebase; or

[0264] (g) Converting a salt of a compound of Formula I, Formula II, orFormula III to another pharmaceutically acceptable salt of a compound ofFormula I, Formula II, or Formula III; or

[0265] (h) Resolving a racemic mixture of a ny proportions of a compoundof Formula I, Formula II, or Formula III to yield a stereoisomer thereof.

[0266] Step (a), above, may be carried out in the presence of an organicsolvent or a mixture of solvents at elevated temperatures. Said org anicsolvent may be toluene, and the reaction may be carried out underrefluxing conditions.

[0267] Step (b), above, may be carried out using the salt of thecompound of the Formula R¹—H in an inorganic solvent. Said salt may bethe lithium, sodium, or potassium salt.

[0268] Step (c), above, may be carried out in an organic solvent or amixture of solvents at elevated temperatures. The haloformylationreagent may be a compound of the formula A-(CO)-B wherein A and B are,independently, suitable leaving groups such as halogens, —COCI, —COBrand the like. The haloformylation agent and organic solvent employed instep (c) may be oxalyl chloride and THF, respectively, and the ensuingreaction may be heated to above 50° C.

[0269] The compounds of the invention can further be synthesized asshown in the following examples. These examples are merely illustrativeof some methods by which the compounds of this invention can besynthesized, and various modifications to these examples can be made andwill be suggested to a person of ordinary skill in the art having regardto this disclosure.

[0270] Procedure A

[0271] Acylurea compounds of the present invention may be preparedstarting with an aryl carboxamide and an isocyanate. Carboxamide andisocyanate starting materials may be purchased from various differentcommercial sources, such as, for example the Aldrich Chemical Company,supra, or they may be prepared from standard procedures known in the artfor preparing these compounds, such as the procedures described in theabove-cited references. The isocyanates may also be prepared accordingto the procedures described in the example below. Typically, an arylcarboxamide is treated with an aryl isocyanate in an organic solvent ormixtures of suitable organic solvents. Preferably, the organic solventis toluene. The carboxamide and the isocyanate may be combined assolutions or suspensions, depending on the solubilities of the compoundsin the selected solvent. The carboxamide and the isocyanate may be addedin a stoichiometric ratio (1:1), or a slight excess of the isocyanatemay be used, for example between 1.01 fold and 2 fold excess, buttypically about 1.01 to about 1.2 fold excess. Typically, the isocyanateis added to a suspension of the carboxamide in toluene, and theresulting mixture is heated until the reaction is determined to becomplete. The reaction mixture may be heated at about 10° C. to about150° C., preferably at about 40° C. to about 120° C. under an inertatmosphere such as nitrogen, or the reaction mixture may be maintainedat the refluxing temperature of the mixture. The reaction may be allowedto proceed to completion in about 10 minutes to 24 hours. Preferably,the reaction is heated to reflux until the reaction is complete, overabout 6 to 24 hours.

[0272] Upon cooling of the reaction mixture, the resulting precipitatedacylureas may be isolated by conventional techniques. Typically, theproduct is isolated by filtration. The precipitated solid may befiltered, washed with a solvent or a series of solvents, and isolatedwithout further purification. Preferably, the precipitated acylureas maybe washed with a combination of toluene, methanol and then with ether,and the product may be dried under vacuum. If desired, the acylureas maybe further purified using conventional techniques, such as bycrystallization using conventional methods known in the art. Optionally,acylureas prepared according to this procedure may be converted to thecorresponding salts prior to isolation and/or purification, or aftercrystallization.

[0273] Procedure B

[0274] Acylureas may also be prepared from the condensation of an arylcarboxamide with an amine. The carboxamide may be prepared from thecorresponding carboxylic acid or may be obtained from commercialsources. Depending on the desired substitution of the amine, optionally,the amine may be substituted where one substituted group is an amineprotecting group such that the protecting group may be removed in asubsequent step if desired. In the first step of the process, acarboxamide mixture in a suitable aprotic solvent is treated with ahaloformylation reagent to form the corresponding carboxamidecarbonylchloride derivative. Typically, the aprotic solvent isdichloromethane, toluene, 2-methyltetrahydrofuran or THF, and thehaloformylation reagent is oxalyl chloride. Preferably, the aproticsolvent is THF. Oxalyl chloride is preferably present in an excess, forexample between 1.1 to 3.0 equivalents, typically about 1.5 equivalentover the carboxamide. The reaction is generally performed under an inertatmosphere where the mixture is heated to 50° C. to 175° C. for 15minutes to 24 hours until the reaction is deemed complete. Typically,the reaction is heated to reflux over 2 to 16 hours under nitrogen, andthen cooled to room temperature. The solvent is removed in vacuo byrotoevaporation or distillation, and the resulting carboxamidecarbonylchloride is then condensed with a primary or secondary amine.Condensation with the amine may be performed by the addition of asolution of the amine in an aprotic solvent, such as THF, under an inertatmosphere, at a temperature between 0° C. and 20° C., preferablybetween 0° C. and 5° C. If the chloroformylation and the subsequentcondensation reaction is performed in the same solvent, the solventremoval step may be eliminated. Preferably, the reaction is performed at0° C. to 5 ° C for 1 to 24 hours, until the reaction is complete. Thesolvent is removed by concentration under reduced pressure, and theacylurea can be isolated by conventional techniques such as filtrationand washing of the crude product with a solvent, followed by dryingunder vacuum.

[0275] Procedure C

[0276] The preparation of the acylureas may also be performed startingwith an amine or aniline derivative through a condensation reaction witha phosgene equivalent, followed by a condensation reaction with thecarboxamide. Typically, a solution of an aniline or aniline derivativeand triphosgene in tetrachloroethane or other suitable organic solventis combined and stirred at 25° C. to 80° C. under an inert atmospherefor 2 to 12 hours until the reaction is complete. The solvent is removedunder reduced pressure and the residue is dissolved in an aproticsolvent, such as toluene, and the resulting mixture is treated with acarboxamide. The mixture is heated to about 50° C. to 150° C.,preferably from about 75° C. to 115° C. Preferably, the reaction mixtureis heated to reflux for 2 to 24 hours until the reaction is complete,and allowed to cool to room temperature. The, precipitated solid isisolated by conventional techniques such as filtration. The filteredsolid is then washed with a suitable solvent or mixtures of solvents.Typically, the solid is washed with toluene, methanol and then ether,and the washed product is dried in vacuo to give the correspondingacylurea.

[0277] Procedure D

[0278] Amino or oxy-substituted aryl acyl ureas of the present inventionmay be prepared starting from the corresponding aryl halide acyl urea bythe reaction of the aryl halide with an amine or alcohol. Preferably,the aryl halide is an aryl chloride, which can be prepared from one ormore of the above described procedures or from standard procedures knownin the art for preparing these compounds. Typically, the acyl urea isdissolved in an organic solvent or a mixture of suitable organicsolvents. Preferably, the organic solvent is tetrahydrofuran. The acylurea and the amine or the alcohol may be combined as solutions orsuspensions, depending on the solubilities of the compounds in theselected solvent or solvent mixtures.

[0279] The acyl urea and the amine or alcohol may be added in astoichiometric ratio (1:1 ), or a slight excess of the amine or alcoholmay be used, for example, between 1.01 fold and 20 fold excess, buttypically about 1.01 to about 10 fold excess. Typically, the amine oralcohol is added to the acyl urea in tetrahydrofuran and the resultingmixture is stirred at about 0° C. to refluxing temperatures of thesolvent, preferably at about 10° C. to about 50° C., most preferably atabout room temperatures under an inert atmosphere such as nitrogen. Thereaction mixture is maintained at the reaction temperature until thereaction proceeds to completion. The reaction may be allowed to proceedto completion in about 10 minutes to 48 hours. Preferably, the reactionis stirred at room temperature for about 5 hours. When the reaction isdeemed complete, the resulting product may be isolated by conventionaltechniques. Typically, the solvent and excess amine or alcohol may beremoved by evaporation under reduced pressure, and the residue issuspended in a solvent. Preferably, the solvent is water. The suspensionor solid may be filtered and washed with water or a suitable solvent,and then isolated and dried using conventional methods.

[0280] Procedure E

[0281] Cyclic acyl ureas of the present invention may be preparedaccording to methods known in the art. One method comprises thealkylation of the acyl urea nitrogens with an alkylating agentgenerically represented above as X—(CH₂)₂₋₄—Y, where X and Y are leavinggroups, and may be the same or different. Leaving groups known in theart include halides, methanesulfonates, trifluoromethanesulfonates,p-toluenesulfonates, p-bromotoluenesulfonate, p-nitrobenzenesulfonatesand the like. Representative alkylating agents include 1,2-dibromoethane, 1,3-dibromoethane, 1,3-dibromopropane, and thecorresponding sulfonates and mixed halosulfonates.

[0282] Typically, the acyl urea is treated with a base in an organicsolvent or mixtures of solvents. Preferably, the base is an inorganicbase such as sodium hydride, or an organic base such as dimethylsulfoxide and sodium hydride. Preferably, the solvent is a polar,aprotic solvent such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glycols, or mixtures of such solvents. Typically, a solutionor suspension of the acyl urea is slowly added to the base in an organicsolvent at about 0° C. to about 25° C., and the resulting mixture isstirred for about 10 minutes to about 5 hours, preferably about 30minutes. The alkylating agent is added and the mixture is stirred untilthe reaction is deemed complete. Alkylation of both urea nitrogens maybe accomplished in a single step, or may be accomplished sequentially ina two step procedure be exposing the partially alkylated product withthe same or different base. The reaction is then quenched with asolvent, preferably water, and the mixture is extracted multiple timeswith an organic solvent. Preferably, the extracting solvent isdichloromethane. The combined organic extracts are washed with water,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to afford the product, which may be purified using standardconditions known in the art. Purification may be performed by silica gelchromatography in a mixture of organic solvents, such as ethyl acetateand petroleum ether.

Example 1

[0283] 2H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide (6)

[0284] Piperonyloyl chloride (3.02 g) was cooled in an ice bath andtreated with 28-30% aqueous ammonia (30 mL). The ice bath was removedand the mixture stirred at room temperature for 1 h. The solid wascollected by filtration, washed with water and dried under high vacuumto yield 2H-benzo[d]1,3-dioxolane-5-carboxamide. A portion of thismaterial (0.40 g) was suspended in anhydrous dichloromethane (6 mL)under a nitrogen atmosphere and treated with oxalyl chloride (1.8 mL ofa 2M solution in dichloromethane). The mixture was heated at gentlereflux for 16 h and then cooled to room temperature. The solvent wasremoved under reduced pressure and the residue dissolved in anhydroustetrahydrofuran (7.5 mL). An aliquot of this solution (2.5 mL) was addedto an ice-cooled, stirred solution of 3-chloroaniline (85 ItL) inanhydrous tetrahydrofuran (1 mL). The ice-bath was removed and themixture stirred at room temperature for 2 h. The precipitated solid wascollected by filtration, washed with dichloromethane, and dried underhigh vacuum to give the title compound. ¹H NMR (DMSO-d₆) δ 6.16 (s, 2H), 7.06 (d, 1H, J=8.2 Hz), 7.15 (d, 1H, J=7.8 Hz), 7.35 (t, 1H, J=8.0Hz), 7.44 (d, 1H, J=8.3 Hz), 7.59 (d, 1H, J=1.6 Hz), 7.67 (d, 1H, J=8.2Hz), 7.83 (d, 1H, J=2.0 Hz), 10.93 (s, 1H), 10.95 (s, 1H). MS (ESI) m/z317, 319.

Example 2

[0285]N-({[3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)carboxamide (98)

[0286] Sodium hydride (0.77 g of a 60% suspension in mineral oil) waswashed with anhydrous hexane (2×10 mL) under a nitrogen atmosphere andthen suspended in anhydrous N,N-dimethylformamide (DMF, 30 mL). Asolution of indole-6-carboxylic acid (1.01 g) in DMF (20 mL) was addedover 5 min and the solution stirred at room temperature for anadditional 30 min. Iodomethane (1.2 mL) was added and the mixturestirred for 1 h. The solution was poured onto ice and allowed to warm upto room temperature. The resulting solid was collected by filtration,washed with water and dried under high vacuum to afford methyl1-methylindole-6-carboxylate. A potion of this material (0.33 g) wasdissolved in methanol (7 mL) and DMF (1 mL) and treated with 5N aqueoussodium hydroxide solution (2 mL). The mixture was heated at reflux for22 h and then allowed to cool to ambient temperature. The solvent wasevaporated under reduced pressure. The residue was dissolved in water(15 mL) and the solution was cooled in an ice-bath and acidified to pH 4with concentrated HCI. The precipitated solid was collected byfiltration, washed with water and dried under high vacuum to produce1-methylindole-6-carboxylic acid. A portion of this material (0.27 g)was dissolved in DMF (4 mL), and treated with diisopropylethylamine (1.6mL) and ammonia (12 mL of a 0.5M solution in dioxane) under a nitrogenatmosphere. O-Benzotriazol-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.64 g) was added and the mixture stirred at roomtemperature for 20 h. The solvent was removed under reduced pressure.The residue was dissolved in ethyl acetate (50 mL), and the solutionwashed with water, 1M sodium carbonate solution, and brine, and driedover magnesium sulfate. Evaporation of the solvent under reducedpressure produced 1-methylindole-6-carboxamide as an off-white solid. Aportion of this material (0.04 g) was suspended in anhydrous toluene(1.0 mL) under a nitrogen atmosphere, and treated with3,5-bis(trifluoromethyl)phenyl isocyanate (42 μL). The mixture washeated at reflux for 2 h and then allowed to cool to room temperature.The solid was collected by filtration, washed with petroleum ether,dichloromethane and methanol and dried under high vacuum to yield thetitle compound. ¹H NMR (DMSO-d₆) δ 3.91 (s, 3H), 6.55 (d, 1H, J=2.9 Hz),7.62 (d, 1H, J=3.0 Hz), 7.67 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J═8.4 Hz),7.82 (s, 1H), 8.40 (br. s, 3H), 11.14 (br. s, 1H), 11.44 (s, 1H). MS(ESI) m/z428.

Example 3

[0287] Benzoxazol-6-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide(83)

[0288] A solution of 4-amino-3-hydroxybenzoic acid (10.0 g) in 85%formic acid (60 mL) was heated at reflux for 3 h and then cooled to roomtemperature. The precipitated solid was filtered, washed with methanol,and dried under vacuum to produce 4-carbonyl-amino-3-hydroxybenzoicacid. A portion of this material (1.00 g) and zinc chloride (3.76 g)were suspended in m-xylene (135 mL), and treated with 2 drops ofconcentrated sulfuric acid. The reaction mixture was azeotroped for 8 h,cooled to room temperature, and treated with water (20 mL). Theresulting solid was collected by filtration, washed with water, anddried under high vacuum to afford benzoxazole-6-carboxylic acid. Aportion of this material (0.80 g) was suspended in anhydrousdichloromethane (30 mL) under a nitrogen atmosphere and treated withoxalyl chloride (12.3 mL of a 2M solution in dichloromethane) and 1 dropof DMF. This suspension was stirred at room temperature for 16 h. Thesolvent was evaporated under reduced pressure. The residue was suspendedin dichloromethane (20 mL) and poured into an ice-cold 2M solution ofammonia in methanol (122 mL). The mixture was stirred at 0° C. for 1 h,and concentrated under reduced pressure. The solid residue was washedwith dichloromethane and water, and dried under high vacuum to affordbenzoxazole-6 carboxamide. A portion of this material (80 mg) was driedby azeotropic distillation with toluene (5.3 mL) and treated with3-chlorophenyl isocyanate (83.3 mg). The mixture was heated at refluxfor 6 h, allowed to cool to room temperature, and treated with methanol(5 mL). The precipitated solid was collected by filtration, washed withmethanol and dichloromethane, and dried under high vacuum to yield thetitle compound. ¹H NMR (DMSO-d₆) δ 7.18 (d, 1H, J=8.0 Hz), 7.39 (t, 1H,J=8.0 Hz), 7.49 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=1.6 Hz), 7.97 (d, 1H,J=8.4 Hz), 8.09 (dd, 1H, J=8.4, 1.6 Hz), 8.50 (s, 1H), 8.98 (s, 1H),10.90 (s, 1H), 11.24 (s, 1H). MS (ESI) m/z314, 316.

[0289] Compounds of General Formulae Ia, IIa, and IIIa

[0290] The compounds shown in Tables 1 to 11 were prepared either by theprocedures described above or by modifications of these proceduresfamiliar to those skilled in the art. TABLE 1

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 1 H Cl OH H H 334.71 333 2 H Cl Cl H H353.16 351, 353 3 i-Pr H H H i-Pr 368.43 367 4 H H OH H H 300.28 299 5 HCl OMe H H 348.74 347 6 H Cl H H H 318.71 317 7 H H H H H 284.27 283 8OH H H Cl H 334.71 333, 335 9 H F H H H 302.26 301 10 F H H H F 320.25319 11 F F H H H 320.25 319 12 H H F H H 302.26 301 13 H H Cl H H 318.71317 14 H F F H H 320.25 319 15 H H CF₃ H H 352.27 371 16 H CF₃ H H H352.27 351 17 H H NO₂ H H 329.27 328 18 H CF₃ NO₂ H H 397.26 396 19 HCF₃ Cl H H 386.71 385, 387 20 H H Br H H 363.17 361, 363 21 H Br H H H363.17 361, 363 22 H CN H H H 309.30 308 23 Cl H Cl H H 353.16 351, 35324 H H OMe H H 314.30 313 25 H H I H H 410.17 409 26 H I H H H 410.17409 27 H H CONH₂ H H 327.29 327 28 H F CF₃ H H 370.26 369 29 H CF₃ F H H370.26 369 30 H H Ph H H 360.37 359 31 H OCF₃ H H H 368.27 367 32 H SCF₃H H H 384.33 383 33 H CF₃ H CF₃ H 420.26 419 34 H i-Pr H H H 360.37 36035 H Et H H H 312.32 311 36 H OEt H H H 328.32 327 37 H Oi-Pr H H H342.35 341 38 H t-Bu H H H 340.38 339 39 H Ph H H H 360.37 359 40 H ClMe H H 332.74 331, 333 41 H I Me H H 424.19 423 42 H CF₃ Me H H 366.29365 43 H OPh H H H 376.37 375 44 H NO₂ H H H 329.27 328 45 H Cl H Cl H353.16 351, 353 46 H Ac H H H 326.30 325 47 H CO₂Me H H H 342.31 341 48H 1H-1,2,3,4- H H H 325.31 351 tetraazol-5-yl 49 H ethynyl H H H 308.29307 50 Me Cl H H H 332.74 351 51 Me H H Cl H 332.74 331 52 Et Cl H H Et374.82 373 53 Me H H I H 424.19 423 54 H 2-pyridyl H H H 361.36 362 55 H1,3-thiazol-2-yl H H H 367.38 368 56 H 3-thienyl H H H 366.40 365 57 H2-furyl H H H 350.33 349 58 H 2-thienyl H H H 366.40 365

[0291] TABLE 2

Cmpd # R MW MS(m/z) 59 3,4-Methylenedioxyphenyl 328.28 327 605-Trifluoromethyl-1,2,3-thiadiazol-2-yl 360.27 359 615-Chloro-1,3-thiazol-2-yl 325.73 324, 326 626-Chloro-4-methylpyrimidin-2-yl 334.72 333, 335 63 2-Chloro-4-pyridyl319.70 318, 320

[0292] TABLE 3

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 64 H CN H H H 343.73 342 65 H I H H H444.61 443 66 H CF₃ H H H 386.71 385 67 H Oi-Pr H H H 376.79 375 68 HCF₃ F H H 404.70 403

[0293] TABLE 4

Cmpd # R¹ R² MW MS(m/z) 69 Me Me 346.77 347, 349 70 Me H 332.74 ND

[0294] TABLE 5

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 71 H Cl Cl H H 350.16 348, 350 72 H HCl H H 315.72 314 73 H Cl H H H 315.72 314 73 H Br H H H 360.17 358, 36075 H H CF₃ H H 349.27 348 76 H I H H H 407.16 406 77 H CF₃ H H H 349.27348 78 H CF₃ H CF₃ H 417.26 418 79 H H F H H 299.26 298

[0295] TABLE 6 Cmpd # R¹ R² R³ R⁴ OR⁵ MW MS(m/z) 80 H Cl Cl H H 350.16348, 350 81 H H Cl H H 315.72 314 82 H H CF₃ H H 349.27 348 83 H Cl H HH 315.72 314 84 H CF₃ H H H 349.27 348 85 H CF₃ H CF₃ H 417.26 417 86 HOCF₃ H H H 365.27 364 87 H CN H H H 306.28 305 88 H CF₃ F H H 367.26 36689 H Br H H H 360.17 358 90 H CO₂CH₃ H H H 339.30 338 91 H Cl CO₂H H H359.72 358 92 H Cl OCH₂CO₂C H H 479.87 478 H₂Ph 93 H H CO₂H H H 325.27324 94 H CO₂H Cl H H 359.72 358 95 H Cl CO₂Na H H 381.70 358 96 H CO₂NaCl H H 381.70 358 97 H H CO₂Na H H 347.25 ND

[0296] TABLE 7

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 98 H CF₃ H CF₃ H 429.32 428 99 H CF₃ HH H 361.32 360 100 H Cl Cl H H 362.21 360, 362, 364 101 H I H H H 419.22418 102 H CN H H H 318.33 317 103 H CF₃ F H H 379.31 378

[0297] TABLE 8

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 104 H Cl Cl H H 362.21 360, 362, 364105 H Cl H H H 327.77 326, 328 106 H Br H H H 372.22 370, 372 107 H CF₃H CF₃ H 429.32 428 108 H CF₃ F H H 379.31 378

[0298] TABLE 9

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 109 H Cl Cl H H 350.16 348, 350 110 H HCl H H 315.72 314

[0299] TABLE 10

Cmpd # R¹ R² R³ R⁴ R⁵ MW MS(m/z) 111 H Cl Cl H H 351.19 349, 351, 353112 H Cl H H H 316.74 315, 317 113 H H CF3 H H 350.29 349 114 H H F H H300.29 299 115 H H OMe H H 312.32 311

[0300] TABLE 11

Cmpd # R¹ R² R³ R⁴ R⁵ Form MW MS (m/z) 116 H Cl Cl H H Free base 363.20361, 363 117 H Cl Cl H H HCl salt 399.66 361, 363

[0301] The names of the compounds shown in Tables 1 to 11 are given inTable 12. These names were generated with the Chemistry 4-D Draw™software from Cheminnovation Software, Inc. (San Diego, Calif.). TABLE12 Cmpd # IUPAC Name 12H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-hydroxyphenyl)amino]carbonyl}carboxamide22H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide32H-Benzo[d]1,3-dioxolan-5-yl-N-({[2,6-bis(methylethyl)phenyl]amino}carbonyl)carboxamide42H-Benzo[d]1,3-dioxolan-5-yl-N-{[(4-hydroxyphenyl)amino]carbonyl}carboxamide52H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-methoxyphenyl)amino]carbonyl}carboxamide62H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide7 2H-Benzo[d]1,3-dioxolan-5-yl-N-[(phenylamino)carbonyl]carboxamide 82H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-chloro-2-hydroxyphenyl)amino]carbonyl}carboxamide92H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-fluorophenyl)amino]carbonyl}carboxamide102H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(2,6-difluorophenyl)amino]carbonyl}carboxamide112H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(2,3-difluorophenyl)amino]carbonyl}carboxamide122H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide132H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide142H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3,4-difluorophenyl)amino]carbonyl}carboxamide152H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide162H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide172H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-nitrophenyl)amino]carbonyl}carboxamide182H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-nitro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide192H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide202H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-bromophenyl)amino]carbonyl}carboxamide212H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide222H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide232H-Benzo[d]1,3-dioxolan-5-yl-N-{[(2,4-dichlorophenyl)amino]carbonyl}carboxamide242H-Benzo[d]1,3-dioxolan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}carboxamide252H-Benzo[d]1,3-dioxolan-5-yl-N-{[(4-iodophenyl)amino]carbonyl}carboxamide262H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide274-{[(2H-Benzo[d]1,3-dioxolan-5-ylcarbonylamino)carbonyl]amino}benzamide282H-Benzo[d]1,3-dioxolan-5-yl-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide292H-Benzo[d]1,3-dioxolan-5-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide302H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-phenylphenyl)amino]carbonyl}carboxamide312H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide322H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethylthio)phenyl]amino}carbonyl)carboxamide332H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide342H-Benzol3,4-d]1,3-dioxolen-5-yl-N-({[3-(methylethyl)phenyl]amino}carbonyl)carboxamide352H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethylphenyl)amino]carbonyl}carboxamide362H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethoxyphenyl)amino]carbonyl}carboxamide372H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(methylethoxy)phenyl]amino}carbonyl)carboxamide382H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(tert-butyl)phenyl]amino}carbonyl)carboxamide392H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide402H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-4-methylphenyl)amino]carbonyl}carboxamide412H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-iodo-4-methylphenyl)amino]carbonyl}carboxamide422H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-methyl-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide432H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-phenoxyphenyl)amino]carbonyl}carboxamide442H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{((3-nitrophenyl)amino]carbonyl}carboxamide452H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3,5-dichlorophenyl)amino]carbonyl}carboxamide462H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-acetylphenyl)amino]carbonyl}carboxamide47 Methyl3-{[(2H-Benzo[3,4-d]1,3-dioxolen-5-ylcarbonylamino)carbonyl]amino}Benzoate482H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)amino]carbonyl}carboxamide492H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethynylphenyl)amino]carbonyl}carboxamide502H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-2-methylphenyl)amino]carbonyl}carboxamide512H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-chloro-2-methylphenyl)amino]carbonyl}carboxamide522H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-2,6-diethylphenyl)amino]carbonyl}carboxamide532H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-iodo-2-methylphenyl)amino]carbonyl}carboxamide542H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-pyridyl)phenyl)amino]carbonyl}carboxamide552H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}carboxamide562H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(3-thienyl)phenyl)amino]carbonyl}carboxamide572H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-furyl)phenyl)amino]carbonyl}carboxamide582H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-thienyl)phenyl)amino]carbonyl}carboxamide592H-Benzo[d]1,3-dioxolan-5-yl-N-[(2H-Benzo[3,4-d]1,3-dioxolen-5-ylamino)carbonyl]carboxamide602H-Benzo[d]1,3-dioxolan-5-yl-N-({[5-(trifluoromethyl)(1,3,4-thiadiazol-2-yl)]amino}carbonyl)carboxamide612H-Benzo[d]1,3-dioxolan-5-yl-N-{[(5-chloro(1,3-thiazol-2-yl))amino]carbonyl}carboxamide622H-Benzo[d]1,3-dioxolan-5-yl-N-{[(6-chloro-4-methylpyrimidin-2-yl)amino]carbonyl}carboxamide632H-Benzo[d]1,3-dioxolan-5-yl-N-{[(2-chloro(4-pyridyl))amino]carbonyl}carboxamide64(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-{[(3-icyanophenyl)amino]carbonyl}carboxamide65(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-{[(3-iodophenyl)amino]carbonyl}carboxamide66(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide67(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[3-(methylethoxy)phenyl]amino}carbonyl)carboxamide68(6-Chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 692H-Benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chlorophenyl)methylamino]carbonyl}-N-methylcarboxamide702H-Benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}-N-methylcarboxamide71 Benzoxazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide 72Benzoxazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 73Benzoxazol-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide 74Benzoxazol-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide 75Benzoxazol-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide76 Benzoxazol-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide 77Benzoxazol-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide78Benzoxazol-5-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide79 Benzoxazol-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide 80Benzoxazol-6-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide 81Benzoxazol-6-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 82Benzoxazol-6-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide83 Benzoxazol-6-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide 84Benzoxazol-6-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide85Benzoxazol-6-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide86Benzoxazol-6-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide87 Benzoxazol-6-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide 88Benzoxazol-6-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide89 Benzoxazol-6-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide 90Methyl 3-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoate 914-{[(Benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoic acid92 Phenylmethyl2-(4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorophenoxy)acetate93 4-{[(Benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoic acid 945-{[(Benzoxazol-6-ylcarbonylamino)carbonyl]amino)-2-chlorobenzoic acid95 Sodium4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoate 96Sodium5-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoate 97Sodium 4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoate 98N-({[3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)carboxamide99(1-Methylindol-6-yl)-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide100N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide101 N-{[(3-Iodophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide 102N-{[(3-Cyanophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide 103N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)carboxamide104N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide105 N-{[(3-Chlorophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide106 N-{[(3-Bromophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide107N-({[3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-5-yl)carboxamide108N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-5-yl)carboxamide109 Benzotriazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide110 Benzotriazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 111N-{[(3,4-Dichlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-ylcarboxamide112N-{[(3-Chlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-ylcarboxamide1132,3-Dihydrobenzo[b]furan-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide1142,3-Dihydrobenzo[b]furan-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide1152,3-Dihydrobenzo[b]furan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}carboxamide116N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylbenzimidazol-5-yl)carboxamide117N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1-methylbenzimidazol-5-yl)carboxamide,hydrochloride

Example 4

[0302] Inhibition of MCP-1 Induced Chemotaxis

[0303] A 96 well microchemotaxis chamber with a 5 μm-pore size,PVP-coated polycarbonate filter membrane (Neuro Probe Inc., Cabin John,MD) was used for testing, Compounds were prepared as 10 mM stocksolution in DMSO. THP-1 cells (2×10⁶ cells/mL) were labeled with 5 μMCalcein AM containing 0.1% F127 (Molecular Probe, Eugene, Oreg.) at 37°C. for 30 min, and then pretreated with compound at room temperature foran additional 30 min. The lower chamber was loaded with mediumcontaining 12.5 nM hMCP-1. The filter membrane was placed over the lowerchamber, followed by a silicon gasket and the upper chamber. Thepretreated THP-1 cells (4×10⁵ cells/50 μL of RPMI1640 medium perwell)were added to the upper chamber and incubated in 5% CO₂ at 37° C. for 2hr. The migrated cells were determined with a fluorescent plate reader(LJL BioSystems, Sunnyvale, Calif.). Table 13 shows the IC₅₀(concentration of compound that inhibited migration of 50% of the cellsrelative to control) for several compounds of the present invention.TABLE 13 Effect of Selected Compounds on MCP-1 Induced Chemotaxis Cmpd #IC₅₀ (μM) 1 4.284 2 11.833 6 4.170 13 >100 16 0.760 19 13.302 21 3.64022 3.093 23 5.904 25 11.661 26 0.198 29 29.296 31 2.175 33 0.955 370.649 39 2.699 54 0.438 55 0.203 56 0.658 57 10.158 58 3.668 65 8.051 710.857 74 3.674 75 >100 80 0.168 81 3.185 83 1.228 84 1.756 86 0.362 874.629 88 1.720 89 1.207 98 1.353 100 0.598 101 0.536 102 4.488 105 8.962111 8.181

Example 5

[0304] Thioglycollate-Induced Inflammation Model

[0305] 3% Brewer's thioglycollate broth (Difco, Detroit, Mich.) wasinjected into the peritoneal cavity of ICR male mice, followed bysubcutaneous administration of the same dose of test compound after 0 h,3 h and 16 hours post-thioglycollate injection, respectively. After 96h, the number of total elicited cells and MOMA2-positive cells in theperitoneal cavity was analyzed using a flowcytometer (EPICS XL, BeckmanCoulter). The results are shown in Table 14. TABLE 14^(a) Effect ofSelected Compounds on a Thioglycollate-Induced Inflammation Model DoseMOMA2-positive Compound (mg/kg) Total Cells (×10⁶) Cells (×10⁶) Notreatment — 1.8 ± 0.3 1.7 ± 0.3 Control — 13.6 ± 1.1  11.4 ± 0.8  16 108.8 ± 1.5 7.5 ± 1.6 82 10 4.2 ± 0.4 3.2 ± 0.4

Example 6

[0306] Anti-Thy-1 Antibody Induced Nephritis Model

[0307] The efficacy of the compounds of the present invention was alsoevaluated in an animal model of nephritis. This model simulates veryclosely the conditions found in human mesangial proliferativeglomerulonephritis.

[0308] Anti-Thy-1 nephritis was induced by intravenous injection ofanti-Thy-1-antibody to male Wistar rats. The test compound wassubcutaneously administered 2 h before, immediately after, and 5 h afterthe anti-Thy-1 antibody treatment, and then twice a day for thefollowing 2 days. Anti-MCP-1 antibody was intraperitoneally injectedonce a day for 3 days. Seven days after the anti-Thy-1 antibodytreatment, the rats were sacrificed. The kidneys were perfused with 10%formaldehyde in PBS, surgically removed, and immersed in 10%formaldehyde. The kidneys were then embedded in paraffin for glomerularhistopathology or in OCT compound (Miles Inc., Elkhart, Ind.) in liquidnitrogen after immersion in 30% sucrose overnight. Immunohistochemicalstaining was performed with a mouse anti-rat ED-1 monoclonal antibody.Briefly, 5 mm renal sections were prepared and endogenous peroxidaseblocked with 0.3% hydrogen peroxide. The sections were then blocked WithProtein Block (DAKO, Japan) and stained with anti-ED-1 antibody for 45min. The ED-1 antigen was visualized by peroxidase-labeled anti-mouseIgG and diaminobenzidine. The amount of urinary protein was determinedwith the DC protein assay kit (Bio-Rad, Hercules, Calif.). The effect ofa representative test compound on the level of urinary protein excretionand the infiltration of ED-1 positive cells into the glomeruli is shownin Table 15. Table 15^(a) Effect of Compound 80 on Anti-Thy-1 AntibodyInduced Nephritis Dose Urinary Protein Compound (mg/kg) (mg/day) Notreatment —  20.0 ± 3.0** Control — 194.2 ± 46.7 80 1 162.1 ± 42.6

Example 7

[0309] Oral pharmaceutical composition—Solid dosage formulation

[0310] A pharmaceutical composition for oral administration may beprepared by combining the following: % w/w Compound of this invention10.0 Magnesium stearate 0.5 Starch 2.0 (Hydroxypropyl)methylcellulose1.0 Microcrystalline cellulose 86.5

[0311] The mixture may be compressed to tablets, or filled into hardgelatin capsules. The tablet may be coated by applying a suspension offilm former (e.g., (hydroxypropyl)-methylcellulose), pigment (e.g.,titanium dioxide) and plasticiser (e.g., diethyl phthalate) and dryingthe film by evaporation of the solvent. The film coat can comprise 2.0%to 6.0% of the tablet weight, preferably about 3.0%.

Example 8

[0312] Oral pharmaceutical composition preparation—Capsule

[0313] A pharmaceutical composition of a compound of the inventionsuitable for oral administration may also be prepared by combining thefollowing: % w/w Compound of this invention 20 Polyethylene glycol 40080

[0314] The medicinal compound is dispersed or dissolved in the liquidcarrier, with a thickening agent added, if required. The formulation isthen enclosed in a soft gelatin capsule by suitable technology.

Example 9

[0315] Pharmaceutical Composition for Parenteral Administration

[0316] A pharmaceutical composition for parenteral administration may beprepared by combining the following: Preferred Level (%) Compound ofthis invention 1.0 Saline 99.0

[0317] Various modifications and variations of the present inventionwill be apparent to those skilled in the art without departing from thescope and spirit of the invention. Although the invention has beendescribed in connection with specific preferred embodiments, it shouldbe understood that the invention as disclosed should not be undulylimited to such specific embodiments. Various modifications of thedescribed modes for carrying out the invention which are obvious tothose skilled in the art are intended to be within the scope of thisinvention.

We claim:
 1. A compound of Formula I, Formula II, or Formula III:

where: (A) in Formula I; each of W, X and Y is independently selectedfrom CR⁶R⁷, N—R⁷, O, or S provided that at least one of W, X, and Y is anon-carbon ring atom, and at least one of W, X, and Y is a carbon ringatom. (B) in Formula II; W and X are independently selected from C—R⁶and N, and Y is selected from CR⁶R⁷, N—R⁷, O, or S, provided that (i) atleast one of W, X, and Y is a non-carbon ring atom, and (ii) when W isC—R⁶ and X is N, then Y is CR⁶R⁷. (C) in Formula III; W is selected fromCR⁶R⁷, N—R⁷, O, or S, and X and Y are independently selected from C—R⁶and N, provided that (i) at least one of W, X, and Y is a non-carbonring atom, and (ii) when X is N and Y is C—R⁶, then W is CR⁶R⁷. Z is Nor C—R⁸; each R¹, R², R⁶, and R⁸ is independently, hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryi(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR⁹,—SR⁹, —NR⁹R¹⁰, —NR⁹(carboxy(lower alkyl)), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —OSO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, heteroaryl(loweralkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted byone O, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl))or N-(optionally substituted C₁₋₂ alkyl) group, R³ and R⁴ are,independently, hydrogen, lower alkyl optionally substituted lower alkyl,optionally substituted aryl, or optionally substituted aryl(loweralkyl), or, together, are —(CH₂)₂₋₄—; R⁵ is hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted aryl(lower alkyl), optionally substitutedheteroaryl, optionally substituted heteroaryl(lower alkyl), C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹²are independently, hydrogen, optionally substituted lower alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹² togetherare —(CH₂)₄₋₆—, each R⁷ is hydrogen, optionally substituted lower alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),—C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ andR¹⁰ are independently, hydrogen, optionally substituted lower alkyl,lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(loweralkyl), aryl(lower alkyl), optionally substituted aryl, optionallysubstituted heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group, or a pharmaceutically acceptable saltthereof, as a single stereoisomer or mixture of stereoisomers.
 2. Thecompound of claim 1, wherein said compound is a compound of Formula I ora pharmaceutically acceptable salt thereof, as a single stereoisomer ormixture of stereoisomers.
 3. The compound of claim 1, wherein saidcompound is a compound of Formula II or a pharmaceutically acceptablesalt thereof, as a single stereoisomer or mixture of stereoisomers. 4.The compound of claim 1, wherein said compound is a compound of FormulaIII or a pharmaceutically acceptable salt thereof, as a singlestereoisomer or mixture of stereoisomers.
 5. The compound of claim 1that is a compound of Formula Ia, Formula IIa, or Formula IIIa:

where: (A) in Formula Ia; each of W, X and Y is independently selectedfrom CR⁶R⁷, N—R⁷, O, or S provided that at least one of W, X, and Y is anon-carbon ring atom, and at least one of W, X, and Y is a carbon ringatom. (B) in Formula IIa; W and X are independently selected from C—R⁶and N, and Y is selected from CR⁶R⁷, N—R⁷, O, or S, provided that (i) atleast one of W, X, and Y is a non-carbon ring atom, and (ii) when W isC—R⁶ and X is N, then Y is CR⁶R⁷. (C) in Formula IIIa; W is selectedfrom CR⁶R⁷, N—R⁷, O, or S, and X and Y are independently selected fromC—R⁶ and N, provided that (i) at least one of W, X, and Y is anon-carbon ring atom, and (ii) when X is N and Y is C—R⁶, then W isCR⁶R⁷. Z is N or C—R⁸; R¹, R², R³ , R⁴, R⁶, R⁷ and R⁸ are as defined inclaim
 1. R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl,optionally substituted aryl, optionally substituted aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN,—OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶,—OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —NR¹⁵SO₂R¹⁶ or —NR¹⁵C(═O)R¹⁶, whereinR¹⁵ and R¹⁶ are independently, hydrogen, optionally substituted loweralkyl, alkenyl, alkynyl, —CF₃, halo(lower alkyl), cycloalkyl, optionallysubstituted heterocycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, each R¹⁴is independently selected from optionally substituted lower alkyl,optionally substituted aryl, optionally substituted heteroaryl, hydroxy,halogen, —CF₃,—OR¹⁷,—NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷,—O(CH₂)_(m)C(═O)OR¹⁷ wherein m is an integer of I to 4, or—C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently, hydrogen, loweralkyl, alkenyl, alkynyl, —CF₃, optionally substituted heterocycloalkyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—,optionally interrupted by one O, S, NH or N—(C₁₋₂ alkyl) group, andwhere n is an integer of 0 to 4, or a pharmaceutically acceptable saltthereof, as a single stereoisomer or mixture of stereoisomers.
 6. Thecompound of claim 5, wherein said compound is a compound of Formula Iaor a pharmaceutically acceptable salt thereof, as a single stereoisomeror mixture of stereoisomers.
 7. The compound of claim 5, wherein saidcompound is a compound of Formula IIa or a pharmaceutically acceptablesalt thereof, as a single stereolsomer or mixture of stereoisomers. 8.The compound of claim 5, wherein said compound is a compound of FormulaIIIa or a pharmaceutically acceptable salt thereof, as a singlestereoisomer or mixture of stereoisomers.
 9. The compound of claim 2 orclaim 6, where W and Y are O, X is CR⁶R⁷, where R⁶ and R⁷ areindependently hydrogen, lower alkyl, or optionally substituted aryl, andZ is C—H.
 10. The compound of claim 3 or claim 7, where W is N. X isCR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl,Y is O, and Z is C—H.
 11. The compound of claim 4 or claim 8, where W isO, X is CR⁶, where R⁶is hydrogen, lower alkyl, or optionally substitutedaryl, Y is N, and Z is C—H.
 12. The compound of claim 4 or claim 8,where W is N—R⁷, where R7 is hydrogen, optionally substituted loweralkyl, or optionally substituted aryl(lower alkyl), X and Y are eachCR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substituted aryl,and Z is C—H.
 13. The compound of claim 3 or claim 7, where W and X areeach CR⁶, where R⁶is hydrogen, lower alkyl, or optionally substitutedaryl, Y is N—R⁷, where R⁷ is hydrogen, lower alkyl, substituted loweralkyl, or optionally substituted aryl(lower alkyl), and Z is C—H. 14.The compound of claim 3 or claim 7, where W and X are each N, Y is N—R⁷,where R⁷ is hydrogen, lower alkyl, substituted lower alkyl, oroptionally substituted aryl(lower alkyl), and Z is C—H.
 15. The compoundof claim 2 or claim 6, where W and X are each CR⁶R⁷, where R⁶ and R⁷ areindependently hydrogen, lower alkyl, or optionally substituted aryl, Yis O, and Z is C—H.
 16. The compound of claim 2 or claim 6, where W isO, X and Y are each CR⁶R⁷, where R⁶ and R⁷ are independently hydrogen,lower alkyl, or optionally substituted aryl, and Z is C—H.
 17. Thecompound of claim 3 or claim 7, where W is N, X is CR⁶, where R⁶ ishydrogen, lower alkyl, or optionally substituted aryl, Y is N—R⁷, whereR⁷ is hydrogen, lower alkyl, substituted lower alkyl, or optionallysubstituted aryl(lower alkyl), and Z is C—H.
 18. The compound of claim 4or claim 8, where W is N—R⁷, where R⁷ is hydrogen, lower alkyl,substituted lower alkyl, or optionally substituted aryl(lower alkyl), Xis CR⁶, where R⁶ is hydrogen, lower alkyl, or optionally substitutedaryl, Y is N, and Z is C—H.
 19. The compound of claim 4 or claim 8,where W is N—R⁷, where R⁷ is hydrogen, flower alkyl, substituted loweralkyl, or optionally substituted aryl(lower alkyl), X and Y areeach N,and Z is C—H.
 20. The compound of claim 1 or claim 5, where R¹ and R²are independently selected from hydrogen, lower alkyl, halogen,optionally lower alkyl substituted heterocycloalkyl, —OR⁹, —SR⁹, or—NR⁹R¹⁰, wherein R⁹ and R¹⁰ are hydrogen, lower alkyl or optionallysubstituted aryl.
 21. The compound of claim 1 or claim 5, where R³ andR⁴ are independently selected from hydrogen or lower alkyl.
 22. Thecompound of claim 2 or claim 6, where W and X are each CR⁶R⁷, where R⁶and R⁷ are independently hydrogen, lower alkyl, or optionallysubstituted aryl, and Z is N—R⁷.
 23. The compound of claim 2 or claim 6,where W is CR⁶R⁷, where R⁶ and R⁷ are independently hydrogen, loweralkyl, or optionally substituted aryl, X is O, and Z is N—R⁷.
 24. Thecompound of claim 2 or claim 6, where W is O, X is CR⁶R⁷, where R⁶ andR⁷ are independently hydrogen, lower alkyl, or optionally substitutedaryl, and Y is N—R⁷.
 25. The compound of claim 5, where R¹³ isindependently selected from alkynyl, optionally substituted aryl,optionally substituted heteroaryl, halogen, —CF₃, —CN, —OR¹⁵, —C(═O)R¹⁵,—C(═O)OR¹⁵, or —C(═O)NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently,hydrogen, lower alkyl, halo(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, heteroaryl(lower alkyl) or R¹⁵ andR¹⁶ together are —(CH₂)₄₋₆—, optionally interrupted by one O, S, NH orN—(C₁₋₂ alkyl) group.
 26. The compound of claim 5, where R¹⁴ isindependently selected from halogen, —CF₃, —OR¹⁷, —C(═O)OR¹⁷,—O(CH₂)_(m)C(═O)OR¹⁷, wherein m is an integer of I to 4, or—C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently, hydrogen, loweralkyl, optionally substituted aryl, heteroaryl, or heteroaryl(loweralkyl), or R¹⁷ and R¹⁸ together are —(CH₂)₄₋₆—, optionally interruptedby one O, S, NH or N-(C₁₋₂ alkyl) group.
 27. The compound of claim 1,where R¹ is hydrogen, optionally substituted lower alkyl, cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, —NR⁹[carboxy(lower alkyl)], —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰ or —NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.28. The compound of claim 1, where R² is hydrogen, optionallysubstituted lower alkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aryl(lower alkyl), halo(lower alkyl), halogen,—OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen,_optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-[aryl(lower alkyl)],N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.29. The compound of claim 1 or claim 5, where R³ and R4 areindependently, hydrogen or lower alkyl.
 30. The compound of claim 1,where R5 and R⁷ are independently hydrogen, optionally substituted loweralkyl, optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), —C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or—SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted aryl, heteroaryl, or heteroaryl(lower alkyl).
 31. Thecompound of claim 1, where R⁸ is hydrogen, optionally substituted loweralkyl, optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, —OR⁹, —NR⁹R¹⁰,—C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —SO₂NR⁹R¹⁰,—NR⁹SO₂R¹⁰ or —NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently,hydrogen, optionally substituted lower alkyl, lower alkyl-N(C₁₋₂alkyl)₂, optionally substituted cycloalkyl, cycloalkyl(lower alkyl),optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R⁹and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.
 32. The compound of claim1, where R¹, R³ and R⁴ are hydrogen, and R⁵ is optionally substitutedaryl or optionally substituted heteroaryl.
 33. The compound of claim 1,where R¹, R², and R⁸ are optionally substituted lower alkyl, cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, ×NR⁹[carboxy(lower alkyl)], —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, lower alkyl, or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 34. The compound of claim 5, where R¹³ ishydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,heterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heteroaryl(lower alkyl), halo(loweralkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵,—C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,cycloalkyl, or halo(lower alkyl).
 35. The compound of claim 5, whereeach R¹⁴ is independently selected from optionally substituted loweralkyl, optionally substituted aryl, optionally substituted heteroaryl,hydroxy, halogen, —CF₃, —OR¹⁷ —NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷,—O(CH₂)_(m)C(═O)OR¹⁷ wherein m is an integer of 1 to 4, —C(═O)NR¹⁷R¹⁸,wherein R¹⁷ and R¹⁸ are, independently, hydrogen, lower alkyl, alkenyl,or optionally substituted aryl.
 36. The compound of claim 1 that isselected from:2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro4-hydroxyphenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(2,6-bis(methylethyl)phenyl]amino}carbonyl)-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-hydroxyphenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chloro-4-methoxyphenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-[(phenylamino)carbonyl]carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-chloro-2-hydroxyphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-fluorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(2,6-difluorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(2,3-difluorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3,4-difluorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-nitrophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-nitro-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-bromophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-bromophenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(2,4-dichlorophenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(4-iodophenyl)amino]carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide;4-{[(2H-benzo[d]1,3-dioxolan-5-ylcarbonylamino)carbonyl]amino}benzamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(4-phenylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethoxy)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(trifluoromethylthio)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3,5-bis(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(methylethyl)phenyl]amino}carbonyl)-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethoxyphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(methylethoxy)phenyl]amino}carbonyl)-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[3-(tert-butyl)phenyl]amino}carbonyl)-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-phenylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-4-methylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-iodo-4-methylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-({[4-methyl-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-phenoxyphenyl)amino]carboriyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-n itrophenyl)amino]carbonyl}-carboxamide; 2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3,5-dichlorophenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-acetylphenyl)amino]carbonyl}-carboxamide;methyl3-{[(2H-benzo[3,4-d]1,3-dioxolen-5-ylcarbonylamino)carbonyl]amino}-benzoate;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)amino]-carbonyl}carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-ethynylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-2-methylphenyl)amino]-carbonyl}carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-chloro-2-methylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chloro-2,6-diethylphenyl)amino]-carbonyl}carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(5-iodo-2-methylphenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-pyridyl)phenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(3-thienyl)phenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-furyl)phenyl)amino]carbonyl}-carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-(2-thienyl)phenyl)amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-[(2H-Benzo[3,4-d]1,3-dioxolen-5-ylamino)-carbonyl]carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-({[5-(trifluoromethyl)(1,3,4-thiadiazol-2-yl)]-amino}carbonyl)carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(5-chloro(1,3-thiazol-2-yl))amino]carbonyl}-carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(6-chloro-4-methylpyrimidin-2-yl)amino]-carbonyl}carboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(2-chloro(4-pyridyl))amino]carbonyl}-carboxamide;(6-bhloro(2H-benzo[3,4-d]1,3-dioxolen-5-yi))-N-{[(3-icyanophenyl)amino]-carbonyl}carboxamide;(6-chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-{[(3-iodophenyl)amino]carbonyl}-carboxamide;(6-chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[3-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide;(6-chloro(2H-benzo[3,4-d]1,3-dioxolen-5-yl))-N-({[3-(methylethoxy)phenyl]amino}-carbonyl)carboxamide;(6-chloro(2 H-benzo[3,4-d]1,3-d ioxolen-5-yl ))-N-({[4-fluoro-3-(trifluoromethyl )-phenyl]amino}carbonyl)carboxamide;2H-benzo[3,4-d]1,3-dioxolen-5-yl-N-{[(3-chlorophenyl)methylamino]carbonyl}-N-methylcarboxamide;2H-benzo[d]1,3-dioxolan-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}-N-methyl-carboxamide;benzoxazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide;benzoxazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;benzoxazol-5-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;benzoxazol-5-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide;benzoxazol-5-yl-N-({[4-(trifluoromethyl )phenyl]amino}carbonyl )carboxamide; benzoxazol-5-yl-N-{[(3-iodophenyl)amino]carbonyl}carboxamide;benzoxazol-5-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;benzoxazol-5-yl-N-({[(tiluorophenyl)amino]carbonyl}carboxamidbenzoxazol-5-yl-N-{[(3,4-diorophenyl)amino]carbonyl}carboxamide;benzoxazol-6-yl-N-{[(3,4-dchlorophenyl)amino]carbonyl}carboxamide;benzoxazol-6-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;benzoxazol-6-yl-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;benzoxazol-6-yl-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;benzoxazol-6-yl-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide;benzoxazol-6-yl-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide;benzoxazol-6-yl-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyllo)-carboxamide;benzoxazol-6-yl-N-{[(3-bromophenyl)amino]carbonyl}carboxamide; methyl3-{[(benzoxazol-6-ylcarbonylamino)carbonyl]aminno}benzoate;4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}2chlorobenzoic acid;phenylmetnyl2-(4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]aminode}-2-chlorophenoxy)acetate;4-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}benzoic acid;5-{[(benzoxazol-6-ylcarbonylamino)carbonyl]amino}-2-chlorobenzoic acid;N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)-carboxamide; (1-methylindol-6-yl)-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide;N-{[(3-iodophenyl)amino]carbonyl}( 1-methylindol-6-yl)carboxamide;N-{[(3-cyanophenyl)amino]carbonyl}(1-methylindol-6-yl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl)-carboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide;N-{[(3-chlorophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide;N-{[(3-bromophenyl)amino]carbonyl}(1-methylindol-5-yl)carboxamide;N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-5-yl)-carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-5-yl)-carboxamide;benzotriazol-5-yl-N-{[(3,4-dichlorophenyl)amino]carbonyl}carboxamide;benzotriazol-5-yl-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-yl-carboxamide;N-{[(3-chlorophenyl)amino]carbonyl}-2,3-dihydrobenzo[b]furan-5-yl-carboxamide;2,3-dihydrobenzo[b]furan-5-yl-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamide;2,3-dihydrobenzo[b]furan-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide;2,3-Dihydrobenzo[b]furan-5-yl-N-{[(4-methoxyphenyl)amino]carbonyl}-carboxamide;andN-{[(3,4-dichlorophenyl)amino]carbonyl}(1-methylbenzimidazol-5-yl)carboxamide;and the pharmaceutically acceptable salts thereof, as singlestereoisomers or mixtures of stereoisomers.
 37. A pharmaceuticalcomposition comprising: (a) a therapeutically effective amount of acompound of claim 1; and (b) a pharmaceutically acceptable excipient.38. The pharmaceutical composition of claim 37, further comprising ananti-inflammatory drug, cytokine, or immunomodulator.
 39. A method oftreating an allergic, inflammatory, or autoimmune disorder or disease,comprising administering a therapeutically effective amount of acompound of claim 1 to a mammal in need of such treatment.
 40. Themethod of claim 39 wherein the compound is administered in combinationwith an.anti-inflammatory drug, cytokine, or immunomodulator.
 41. Themethod of claim 39 wherein the allergic, inflammatory, or autoimmunedisorder or disease is selected from the group consisting of asthma,atherosclerosis, glomerulonephritis, pancreatitis, restenosis,rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis,inflammatory bowel disease, Crohn's disease, and transplant rejection.42. The method of claim 39 where the allergic, inflammatory, orautoimmune disorder or disease is asthma.
 43. The method of claim 39where the allergic, inflammatory, or autoimmune disorder or disease isatherosclerosis.
 44. The method of claim 39 where the allergic,inflammatory, or autoimmune disorder or disease is glomerulonephritis.45. The method of claim 39 where the allergic, inflammatory, orautoimmune disorder or disease is pancreatitis.
 46. The method of claim39 where the allergic, inflammatory, or autoimmune disorder or diseaseis restenosis.
 47. The method of claim 39 where the allergic,inflammatory, or autoimmune disorder or disease is rheumatoid arthritis.48. The method of claim 39 where the allergic, inflammatory, orautoimmune disorder or disease is diabetic nephropathy.
 49. The methodof claim 39 where the allergic, inflammatory, or autoimmune disorder ordisease is pulmonary fibrosis.
 50. The method of claim 39 where theallergic, inflammatory, or autoimmune disorder or disease isinflammatory bowel disease.
 51. The method of claim 39 where theallergic, inflammatory, or autoimmune disorder or disease is Crohn'sdisease.
 52. The method of claim 39 where the allergic, inflammatory, orautoimmune disorder or disease is transplant rejection.
 53. The methodof claim 39 wherein the allergic, inflammatory, or autoimmune disorderor disease is associated with lymphocyte and/or monocyte accumulation.54. A method of inhibiting leukocyte migration, comprising administeringa therapeutically effective amount of a compound of claim 1 to a mammalin need of such treatment.